Heterocyclic compounds and anticancer-drug potentiaters conaining them as effective components

ABSTRACT

Novel heterocyclic compounds, which are represented by the following general formula, useful as anticancer drug potentiaters having a potentiating effect on the incorporation of anticancer drugs into cancer cells, the compounds each synthesized by, for example, reacting a epoxy compound obtained by reacting a heterocyclic compound with an epihalogenohydrin, with an amine derivative.

This is a division of application Ser. No. 07/417,780, filed Oct. 6,1989, now U.S. Pat. No. 5,112,817.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds and anticancer drugpotentiaters containing them as effective components.

2. Description of the Prior Art

Since the number of cancer patients is increasing year after year andcancer is the leading death cause today in many countries, cancertreatment is of great social interest.

Research and development regarding anticancer drugs for cancer treatmenthave been actively pursued and various anticancer drugs have beenclinically used for therapeutic benefit. The effect of these agentssteadily improves from year to year. However, in many cases, the agentsdo not necessarily completely control cancer growth and prolong the lifeof cancer patients. Furthermore, the use of multiple anticancer drugs incombination (multiple-drug treatment) have been tried in variousclinical cases. However, likewise, the resulting effect is not entirelysatisfactory cancer chemotherapy. Thus, development of novel therapeuticagents for the treatment of cancer from a fresh viewpoint is needed.

Development of more effective anticancer drugs or of means to deliveranticancer drugs more selectively to the target organs and tissuecontinues. Today, various research activities directed towards thesegoals are being conducted in many places throughout the world but onlywith increasing difficulty.

Another important aspect of cancer chemotherapy is potentiating theeffects of chemotherapeutic agents. Development of potentiaters tofacilitate presently available anticancer drugs, in particular formultiple drug-resistant cancers which is a serious clinical problem incancer chemotherapy, is considered to be extremely important in cancertherapy. The background of the clinical incidence of resistance ofcancer to anticancer drugs is complex. Clinically, two aspects aregenerally considered. The first is where the resistance is attributed toindividual cancer patients. The second is where the resistance isattributed to cancer cells per se. Recently, as to the second aspect,the mechanism of tumor cell resistance has been elucidated at amolecular level and accordingly methods for therapy of this type ofcancer resistance have been under investigation. Namely, a gene which isresponsible for multi-drug-resistance has been recently isolated. It hasbeen determined that this gene codes for a membrane protein,P-glycoprotein, and is expressed in multi-drug-resistant cells. It issuspected that the P-glycoprotein functions by promoting extracellularexcretion of anticancer drugs and plays the central role in themechanism of multiple-drug-resistance. Furthermore, it is suggested thatthe mechanism is partly common to that of the resistance to solid cancerwhich is by itself resistant to anticancer drugs.

Anticancer drugs primarily pass into the cell membrane to manifest theireffect inside the cells; however, in drug-resistant cancer cells,anticancer drugs are discharged outside the cells due to the function ofthe P-glycoprotein, so that the drug concentration inside the cancercells remains low. Consequently, the effect of the anticancer drugs isnot exhibited to the fullest extent possible.

Accordingly, the present inventors consider that substances which cansuppress the function of the P-glycoprotein so as to interfere with theoutflow of anticancer drugs from cancer cells have ability to potentiatethe effect of anticancer drugs and are particularly effective inovercoming drug resistance and thus make promising novel cancerchemotherapeutics.

In fact, Tsuruo et al. found that calcium antagonists such as verapamilprevent discharge of anticancer drugs from cancer cells and that,accordingly with the use of these calcium antagonists in combination,the effect of anticancer drugs such as adriamycin and vincristine ondrug-resistant cancer cells is reinforced in vitro and in vivo. However,in the case where these calcium antagonists are used clinically forcancer patients, side effects such as hypotonia and arhythmia occur,which creates another serious problem in cancer chemotherapy.Consequently, drugs which have a stronger potentiating activity foranticancer drugs against drug-resistant cancers and manifest fewer sideeffects are desired.

SUMMARY OF THE INVENTION

As a result of intensive investigations in view of above-mentionedproblems, the present inventors found that certain compounds manifeststrong activity to potentiate the effects of anticancer drugs when usedagainst drug-resistant cancer and have low toxicity and fewer sideeffects, and thus completed the present invention.

The present invention relates compounds within the following generalformula [I] and salts thereof (hereinafter referred to as the compoundsaccording to the present invention) and to therapeutic compositions topotentiate the effect of anticancer drugs containing the compoundsaccording to the present invention as active ingredients: ##STR1## inwhich A represents an oxygen or sulfur atom or a methylene, amino or--NR³ group, which is bound to any one of the available sites on thecondensed ring, B represents --(CH₂)_(n) --, ##STR2## or --CO(CH₂)_(n)--, C represents ##STR3## D represents ##STR4## or C and D together form##STR5## E, F, G and H each independently represent a carbon or nitrogenatom, provided at least one atom is nitrogen. R¹ and R² eachindependently represent a hydrogen or halogen atom, a lower alkyl, aminogroup, substituted amino group, a lower alkoxy, lower alkylthio, loweralkylsulfonyl, trifluoromethyl, cyano, nitro, amide or hydroxy group, R¹and R² may be substituted on any of the possible sites on the condensedring and may be one on each of the two rings of which the condensed ringconsists or two at the same time on one of the rings. R³ represents ahydrogen atom or a lower alkyl or acyl group. R⁴ represents a hydroxyl,lower alkylamino, lower alkoxyl or lower acyloxy group, R⁵ and R⁶ eachindependently represent a hydrogen atom or a lower alkyl or hydroxyalkylgroup, R⁷, R⁸ and R⁹ each independently represent a hydrogen atom or ahydroxy, phenyl, pyridyl or substituted phenyl group, I represents anoxygen atom, --(CH₂)_(m) -- ##STR6## or a nitrogen atom, J represents--(CH₂)_(m) --, --CH═CH--, --OCH₂ -- or an oxygen atom, n represents anintegral number in the range between 1 and 10, and m represents anintegral number, 0, 1 or 2.

The compounds according to the present invention significantly suppressthe outflow of anticancer drugs from cancer cells and, moreover, arecharacterized by their low toxicity and extremely low incidence of sideeffects to the patient such as hypotonia.

Accordingly, the compounds according to the present invention areeffective to facilitate retenting anticancer drugs in cancer cells,which cells are less sensitive or resistant to anticancer drugs, and canthus provide new therapeutic means advance cancer chemotherapy.

DETAILED DESCRIPTION AND THE PREFERRED EMBODIMENTS

As used herein, the terms used above have the following meanings: ahalogen atom means a fluorine atom, chlorine atom, bromine atom oriodine atom.

A lower alkyl group means a methyl group, ethyl group, propyl group,butyl group, their positional isomers or the like.

A substituted amino group means a methylamino group, dimethylaminogroup, ethylamino group, diethylamino group, propylamino group,butylamino group or the like.

A lower alkoxy group means a methoxy group, ethoxy group, propoxy group,butoxy group or the like.

An amido group means a formamido group, acetamido group, benzamido groupor the like.

An acyl group means a formyl group, acetyl group, propanoyl group,benzoyl group or the like.

An acyloxy group means a formyloxy group, acetoxy group or the like.

A hydroxyalkyl group means a 2-hydroxyethyl group, 2-hydroxypropyl groupor 3-hydroxypropyl group or the like.

A substituted phenyl group means a halogenophenyl group, alkoxyphenylgroup, aminophenyl group, alkylaminophenyl group, acylaminophenyl group,hydroxyphenyl group or the like which is substituted at the 2-, 3- or4-position.

Examples of a partial structure of the general formula (I) representedby the formula ##STR7## include 2-methylquinoline, 3-methylquinoline,4-methylquinoline, 6-methylquinoline, 7-methylquinoline,8-methylquinoline, 2-ethylquinoline, 3-ethylquinoline, 4-ethylquinoline,6-ethylquinoline, 7-ethylquinoline, 8-ethylquinoline,2,4-dimethylquinoline, 2,4-diethylquinoline, 7-nitroquinoline,8-nitroquinoline, 2-methoxyquinoline, 3-methoxyquinoline,4-methoxyquinoline, 6-methoxyquinoline, 7-methoxyquinoline,8-methoxyquinoline, 2-chloroquinoline, 3-chloroquinoline,4-chloroquinoline, 6-chloroquinoline, 7-chloroquinoline,8-chloroquinoline, 2-trifluoromethylquinoline,3-trifluoromethylquinoline, 4-trifluoromethylquinoline,6-trifluoromethylquinoline, 7-trifluoromethylquinoline,8-trifluoromethylquinoline, 2,4-bis(trifluoromethyl)quinoline,2-fluoroquinoline, 3-fluoroquinoline, 4-fluoroquinoline,6-fluoroquinoline, 7-fluoroquinoline, 8-fluoroquinoline,2-bromoquinoline, 3-bromoquinoline, 4-bromoquinoline, 6-bromoquinoline,7-bromoquinoline, 8-bromoquinoline, 2-iodoquinoline, 8-iodoquinoline,2-propylquinoline, 3-propylquinoline, 2,4-dipropylquinoline,8-propylquinoline 2-butylquinoline, 8-butylquinoline,2,4-dibutylquinoline, 2-aminoquinoline, 7-aminoquinoline,8-aminoquinoline, 2-methylaminoquinoline, 7-methylaminoquinoline,8-methylaminoquinoline, 2-dimethylaminoquinoline,7-dimethylamoinoquinoline, 8-dimethylaminoquinoline,2-ethylaminoquinoline, 8-ethylaminoquinoline, 2-diethylaminoquinoline,8-diethylaminoquinoline, 2-propylaminoquinoline, 8-propylaminoquinoline,2-ethoxyquinoline, 7-ethoxyquinoline, 8-ethoxyquinoline,2-propoxyquinoline, 7-propoxyquinoline, 2-butoxyquinoline,8-butoxyquinoline, 2-cyanoquinoline, 2-formamidoquinoline,2-acetamidoquinoline, 7-acetamidoquinoline, 8-acetamidequinoline,3-hydroxyquinoline, 7-hydroxyquinoline, 8-hydroxyquinoline,isoquinoline, quinoxaline, quinazoline and cinnoline.

Examples of A, which is a partial structure of the general formula (I),include an oxygen atom --O--, sulfur atom --S--, methylene group --CH₂--, amino group --NH--, methylamino group --N(CH₃)--, ethylamino group--N(CH₂ CH₃)--, propylamino group --N(CH₂ CH₂ CH₃)--, butylamino group--N(CH₂ CH₂ CH₂ CH₃)--, acetylamino group --N(COCH₃)--, formylaminogroup --N(CHO)--, propanoylamino group --N(COCH₂ CH₃)-- and benzoylaminogroup --N(COPh)--.

Examples of B, which is also a partial structure of the general formula(I), include --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂ --, --CH₂CH(OH)CH₂ --, --CH₂ CH(OCOCH₃)CH₂ --, --CH₂ CH(OCHO)CH₂ --, --CH₂CH(NH₂)CH₂ --, --CH₂ CH(NHCH₃)CH₂ --, --CH₂ CH(NMe₂)CH₂ --, --CH₂CH(NHCH₂ CH₃)CH₂ --, --CH₂ CH(OCH₃)CH₂ --, --CH₂ CH(OCH₂ CH₃)CH₂ --,--COCH₂ CH₂ --, --COCH₂ CH₂ CH₂ -- and --COCH₂ CH₂ CH₂ CH₂ --.

Examples of C, which also is a partial structure of the general formula(I), include a piperazine ring, homopiperazine ring,N,N'-dimethylethylenediamine, N,N'-diethylethylenediamine, ethylamine,propylamine, N-methylpropylamine and a piperidine ring.

Examples of D, which is also a partial structure of the general formula(I), include a diphenylmethyl group, benzyl group, (4-pyridyl)methylgroup, (3-pyridyl)methyl group, (2-pyridyl)methyl group,phenyl-(2-pyridyl)methyl group, phenyl-(3-pyridyl)methyl group,phenyl-(4-pyridyl)methyl group, di(2-pyridyl)methyl group,di(4-pyridyl)methyl group, diphenyl-hydroxymethyl group, triphenylmethylgroup, (4-chlorophenyl)-phenylmethyl group, bis(4-chlorophenyl)methylgroup, (4-fluorophenyl)-phenylmethyl group, bis(4-fluorophenyl)methylgroup, (4-methoxyphenyl)-phenylmethyl group, bis(4-methoxyphenyl)methylgroup, (4-hydroxyphenyl)phenylmethyl group, bis(4-hydroxyphenyl)methylgroup, (4-dimethylaminophenyl)-phenylmethyl group,(2,3-dimethoxyphenyl)-(3,4-dimethoxyphenyl)methyl group,bis(4-dimethylaminophenyl)methyl group, 5-fluorenyl group,9,10-dihydro-9-anthrasenyl group, 5-dibenzosuberanyl group,6,11-dihydrodibenzo[b,e]oxepine-11-yl group, 5-dibenzosuberenyl group,5-xanthenyl group, diphenylmethoxy group, 5-dibenzosuberanyloxy group,phenyl-(2-pyridyl)methoxy group, phenyl-(3-pyridyl)methoxy group,phenyl-(4-pyridyl)methoxy group, di(2-pyridyl)methoxy group,di(3-pyridyl)methoxy group, di(4-pyridyl)methoxy group,bis(4-methoxyphenyl)methoxy group, bis(4-hydroxyphenyl)methoxy group,bis(4-dimethylaminophenyl)methoxy group,(2,3-dimethoxyphenyl)-(3,4-dimethoxyphenyl)methoxy group,6,11-dihydrodibenzo[b,e]oxepine-11-yloxy group, 5-dibenzosuberenyloxygroup, 5-xanthenyloxy group, 2,2-diphenylethyl group,2,2-di(2-pyridyl)ethyl group, 2,2-di(4-pyridyl)ethyl group,2-phenyl-2-(2-pyridyl)ethyl group, 2-phenyl-2-(3-pyridyl)ethyl group,2-phenyl-2-(4-pyridyl)ethyl group, 2,2-diphenyl-2-hydroxyethyl group,2-(4-chlorophenyl)-2-phenylethyl group, 2,2-bis(4-chlorophenyl)ethylgroup, 2-(4-methoxyphenyl)-2-phenylethyl group,2,2-bis(4-methoxyphenyl)ethyl group, 2-(4-hydroxyphenyl)-2-phenylethylgroup, 2,2-bis(4-hydroxyphenyl)ethyl group,2-(4-dimethylaminophenyl)-2-phenylethyl group,2-(2,3-dimethoxyphenyl)-2-(3,4-dimethoxypheny)ethyl group,(5-dibenzosuberanyl)methyl group, 2,2-diphenylacetyl group,2-phenylacetyl group, 2-(4-pyridyl)acetyl group, 2-(3-pyridyl)acetylgroup, 2-(2-pyridyl)acetyl group, 2-phenyl-2-(2-pyridyl)acetyl group,2-phenyl-2-(3-pyridyl)acetyl group, 2-phenyl-2-(4 -pyridyl)acetyl group,2,2-di(2-pyridyl)acetyl group, 2,2-di(4-pyridyl)acetyl group,2,2,2-triphenylacetyl group, 2-(4-chlorophenyl)-2-phenylacetyl group,2,2-bis(4-chlorophenyl)acetyl group, 2-(4-fluorophenyl)-2-phenylacetylgroup, 2,2-bis(4-fluorophenyl)acetyl group,2-(4-methoxyphenyl)-2-phenylacetyl group, 2,2-bis(4-methoxyphenyl)acetylgroup, 2-(4-hydroxyphenyl)-2-phenylacetyl group,2,2-bis(4-hydroxyphenyl)acetyl group,2-(4-dimethylaminophenyl)-2-phenylacetyl group,2,2-bis(4-dimethylaminophenyl)acetyl group,2-(2,3-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)acetyl group,dibenzosuberane-5-carbonyl group, fluorene-5-carbonyl group,6,11-dihydrobenzo[b,e]oxepine-11-carbonyl group,dibenzosuberene-5-carbonyl group, 5-xanthenecarbonyl group,3,3-diphenylpropyl group, 3-(dibenzosuberane-5-yl)ethyl group,(diphenylmethyl)amino group, 5-dibenzosuberanylamino group,N,N-diphenylamino group, N-phenyl-N-(2-pyridyl)amino group,N-phenyl-N-(3-pyridyl)amino group, N-phenyl-N-(4-pyridyl)amino group,N,N-bis(4-chlorophenyl)amino group, N,N-bis(4-fluorophenyl)amino group,N,N-bis(4-methoxyphenyl)amino group, N,N-bis(4-hydroxyphenyl)aminogroup, 9,10-dihydroacridine-10-yl group,10,11-dihydro-dibenzo[b,f]-azepine-5-yl group, dibenzo[b,f]azepine-5-ylgroup, N,N-diphenylcarbamoyl group, N-phenyl-N-(2-pyridyl)carbamoylgroup, N-phenyl-N-(3-pydidyl)carbamoyl group, N-phenyl-N-(4-pydidyl)carbamoyl group, N,N-bis(4-chlorophenyl)carbamoyl group,N,N-bis(4-fluorophenyl)carbamoyl group,N,N-bis(4-methoxyphenyl)carbamoyl group,N,N-bis(4-hydroxyphenyl)carbamoyl group,9,10-dihydroacridine-10-carbonyl group,10,11-dihydro-dibenzo[b,f]azepine-5-carbonyl group,dibenzo[b,f]azepine-5-carbonyl group and diphenylmethylene group.

Specific examples of compounds represented by general formula (I)include:

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-2-methylquinoline

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-3-methylquinoline

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-4-methylquinoline

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-6-methylquinoline

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-7-methylquinoline

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-8-methylquinoline

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-2-methylquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-3-methylquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-4-methylquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-6-methylquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-7-methylquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-8-methylquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-2-methoxyquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-3-methoxyquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-4-methoxyquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-6-methoxyquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-7-methoxyquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-8-methoxyquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-2-methoxyquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-3-methoxyquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-4-methoxyquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-6-methoxyquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-7-methoxyquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-8-methoxyquinoline,

2-ethyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-ethyl-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-2-propylquinoline

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-2-propylquinoline,

2-butyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-butyl-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)hydroxylpropoxy]quinoline,

2,4-dimethyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2,4-dimethyl-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-7-nitroquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-8-nitroquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-7-nitroquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-8-nitroquinoline,

2-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline

3-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline

4-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline

6-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline

7-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline

8-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline

2-chloro-5-[3-(4-(diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

3-chloro-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

4-chloro-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

6-chloro-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

7-chloro-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

8-chloro-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-2-trifluoromethylquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-4-trifluoromethylquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]-2-trifluoromethylquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-4-trifluoromethylquinoline,

2,4-bis(trifluoromethyl)-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2,4-bis(trifluoromethyl)-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-2-fluoroquinoline

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-4-fluoroquinoline

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-2-fluoroquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-4-fluoroquinoline,

2-bromo-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

3-bromo-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

4-bromo-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-bromo-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

3-bromo-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

4-bromo-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-amino-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-amino-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-2-methylaminoquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-2-methylaminoquinoline,

2-dimethylamino-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-dimethylamino-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-ethoxy-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline

2-ethoxy-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-cyano-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-cyano-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)hydroxylpropoxy]quinoline,

5-[3-4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]-8-hydroxyquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropoxy]-8-hydroxyquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropylthio]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxylpropylthio]quinoline,

5-[4-(4-(diphenylmethylpiperaine-1-yl)butyl]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)butyl]quinoline,

5-[3-(4-(diphenylmethylpiperazine-1-yl)-2-hydroxypropylamino]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropylamino]quinoline,

N-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropyl]-N-methyl-5-quinolineamine,

N-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropyl]-N-methyl-5-quinolineamine,

N-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropyl]-N-acetyl-5-quinolineamine,

N-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropyl]-N-acetyl-5-quinolineamine,

5-[2-(4-diphenylmethylpiperazine-1-yl)ethoxy]quinoline,

5-[2-(4-(dibenzosuberane-5-yl)piperazine-1-yl)ethoxy]quinoline,

5-[4-(4-diphenylmethylpiperazine-1-yl)butoxy]quinoline,

5-[4-(4-(dibenzosuberane-5-yl)piperazine-1-yl)butoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-ylpropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)propoxy]quinoline,

5-[2-acetoxy-3-(4-diphenylmethylpiperazine-1-yl)propoxy]quinoline,

5-[2-acetoxy-3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)propoxy]quinoline,

5-[2-amino-3-(4-diphenylmethylpiperazine-1-yl)propoxy]quinoline,

5-[2-amino-3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)propoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-methylaminopropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-methylaminopropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-methoxypropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-methoxypropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-propionamido]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)propionamido]quinoline,

5-[3- 4-diphenylmethylpiperazine-1-yl)-N-methylpropionamido]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-N-propionamido]quinoline,

5-[3-(4-diphenylmethylhomopiperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)homopiperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[N-(2-(N-diphenylmethyl-N-methylamino)ethyl)-N-methylamino]-2-hydroxypropoxy)quinoline,

5-(3-(N-[2-(N-(dibenzosuberane-5-yl)-N-methylamino)ethyl]-N-methylamino)-2-hydroxypropoxy)quinoline,

5-[3-(4-(diphenyl-hydroxymethyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline

5-[3-(4-(diphenylmethylene)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-diphenylmethylpiperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(diphenyl-hydroxymethyl)piperidine-1-yl)-2-hydroxypropoxy]-2-quinoline,

5-[3-(4-(phenyl-2-pyridylmethyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

5-[3-(4-(phenyl-3-pyridylmethyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

5-[3-(4-(phenyl-4-pyridylmethyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

5-(3-[4-(di-(2-pyridyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(di-(3-pyridyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(di-(4-pyridyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-chlorophenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-fluorophenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-((4-chlorophenyl)-phenylmethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-methoxyphenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-hydroxyphenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-dimethylaminophenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-((2,3-dimethylphenyl)-(3,4-dimethoxyphenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(fluorene-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(9,10-dihydro-9-anthracenyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(6,11-dihydrodibenzo[b,e]oxepine-11-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzosuberene-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(xanthene-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(diphenylmethoxy)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-yloxy)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(phenyl-2-pyridylmethoxy)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(phenyl-3-pyridylmethoxy)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(phenyl-4-pyridylmethoxy)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(di(2-pyridyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(di(3-pyridyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(di(4-pyridyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-chlorophenyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-fluorophenyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-((4-chlorophenyl)-phenylmethoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-methoxyphenyl)-methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-methoxyphenyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-dimethylaminophenyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-((2,3-dimethoxyphenyl)-(3,4-dimethoxyphenyl)methoxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(9,10-dihydro-9-anthracenyloxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(6,11-dihydrodibenzo[b,e]oxepine-11-yloxy)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(dibenzosuberene-5-yloxy)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(xanthene-5-yloxy)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(2,2-diphenylethyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-yl)methylpiperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(2-phenyl-2-(2-pyridyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2-phenyl-2-(3-pyridyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2-phenyl-2-(4-pyridyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-di(2-pyridyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline

5-(3-[4-(2,2-di(3-pyridyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline

5-(3-[4-(2,2-di(4-pyridyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline

5-(3-[4-(2,2-bis(4-chlorophenyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-fluorophenyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-(4-chlorophenyl)-phenylethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-methoxyphenyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-hydroxyphenyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-dimethylaminophenyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2-(2,3-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(fluorene-5-yl)methylpiperazine-1-yl]-2-hydroxypropoxy)quinoline

5-(3-[4-(9,10-dihydro-9-anthracenyl)methylpiperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(6,11-dihydrodibenzo[b,e]oxepine-11-yl)methylpiperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzosuberene-5-yl)methylpiperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(xanthene-5-yl)methylpiperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(diphenylacetyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-carbonyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(phenyl-2-pyridylacetyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline

5-[3-(4-(phenyl-3-pyridylacetyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline

5-[3-(4-(phenyl-4-pyridylacetyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline

5-[3-(4-di-(2-pyridyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(di-(3-pyridyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(di-(4-pyridyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-chlorophenyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-fluorophenyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(4-chlorophenyl)-phenylacetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-methoxyphenyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-hydroxyphenyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-dimethylaminophenyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-((2,3-dimethoxyphenyl)-(3,4-dimethoxyphenyl)acetyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(9,10-dihydro-anthracenyl-9-carbonyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(6,11-dihydrodibenze[b,e]oxepine-11-carbonyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(dibenzosuberene-5-carbonyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(xanthene-5-carbonyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(2,2-diphenylacetyl)piperazine-1-yl)-2-hydroxy-propoxy]quinoline,

5-[3-(4-(dibenzosuberane-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(2-phenyl-2-(2-pyridyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2-phenyl-2-(3-pyridyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2-phenyl-2-(4-pyridyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-di-(2-pyridyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-di(3-pyridyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-di(4-pyridyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-chlorophenyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-fluorophenyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2-(4-chlorophenyl)-2-phenylacetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-methoxyphenyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-hydroxyphenyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2,2-bis(4-dimethylaminophenyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(2-(2,3-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)acetyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(fluorene-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(9,10-dihydroanthracenyl-9-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(6,11-dihydrodibenzo[b,e]oxepine-11-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzosuberene-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(xanthene-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(3,3-diphenylpropyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(2-(5-dibenzosuberanyl)ethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(diphenylmethylamino)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-((5-dibenzosuberanyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(N,N-diphenylamino)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(N-diphenyl-N-(2-pyridyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N-diphenyl-N-(3-pyridyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N-phenyl-N-(4-pyridyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-chlorophenyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-fluorophenyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-methoxyphenyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-hydroxyphenyl)amino)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(9,10-dihydroacridine-10-yl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(10,11-dihydrodibenzo[b,f]azepine-5-yl)piperizine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzo[b,f]azepine-5-yl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(N,N-diphenylcarbamoyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(N-phenyl-N-(2-pyridyl)carbamoyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N-phenyl-N-(3-pyridyl)carbamoyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N-phenyl-N-(4-pyridyl)carbamoyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-chlorophenyl)carbamoyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-fluorophenyl)carbamoyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-methoxyphenyl)carbamoyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(N,N-bis(4-hydroxyphenyl)carbamoyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(9,10-dihydroacridine-10-carbonyl)piperidine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(10,11-dihydrodibenzo[b,f]azepine-5-carbonyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(dibenzo[b,f]azepine-5-carbonyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(diphenylmethylene)piperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]isoquinoline,

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]isoquinoline,

5-[3-(4-diphenylmethylhomopiperazine-1-yl)-2-hydroxypropoxy]isoquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]isoquinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinoxaline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxylpropoxy]quinazoline,

5-(3-[4-((4-pyridyl)phenylmethyl)piperazine-1-yl]-2-hydroxylpropoxy)quinoline,

2,4-dimethyl-5-[3-((α,β-diphenylacetyl)piperazine-1-yl)-2-hydroxylpropoxy]quinoline,

2-trifluoromethyl-4-methyl-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

2-trifluoromethyl-4-methyl-5-[3-(4-(α,α-diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

2-trifluoromethyl-4-methyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-(3-[4-(bis(4-fluorophenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-((4-chlorophenyl)-phenylmethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-(3-[4-(bis(4-methoxyphenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline,

5-[3-(4-(iminodibenzyl-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

2,4-dimethyl-5-[3-(4-(iminodibenzyl-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(N'-(dibenzosuberane-5-yl)ethylenediamino)-2-hydroxypropoxy]quinoline,

5-[3-(N,N'-dimethyl-N'-(dibenzosuberane-5-yl)ethylenediamino)-2-hydroxypropoxy]quinoline,

2-methylthio-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

2-methylthio-5-[3-(4-(α,α-diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

2,4-dimethyl-5-[3-(N,N'-dimethyl-N'-(dibenzosuberane-5-yl)ethylenediamino)-2-hydroxypropoxy]quinoline,

2,4-dimethyl-5-[3-(4-diphenylmethylenepiperidine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(10,11-dihydro-N-methyl-5H-dibenzo[a,d]-cycloheptene-Δ⁵,.gamma.-propylamino)-2-hydroxypropoxy]quinoline,

5-[3-(3,3-diphenylpropylamino)-2-hydroxypropoxy]quinoline,

5-[3-(2,2-diphenylethylamino)-2-hydroxypropoxy]quinoline,

2-methylsulfonyl-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(4-(xanthene-9-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline,

5-[3-(N-methyl-3-(5-iminobenzyl)propylamino)-2-hydroxypropoxy]quinoline,

5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropylthio]quinoline,and

5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropylthio]quinoline.

Salts of the compounds according to the present invention include saltsof inorganic acids such as hydrochloric acid and sulfuric acid as wellas organic salts such as acetic acid, oxalic acid, maleic acid andtartaric acid. Compounds of the present invention have an asymmeticcarbon atom in their structure, and therefore optical isomers exist. Allof these optical isomers are regarded as within the present invention.The compounds of the present invention are prepared as follows: Firstsynthetic method: A heterocyclic compound represented by the followingformula is reacted with a halide such as epichlorohydrin orepibromohydrin in the presence of a base in a solvent at an appropriatetemperature in order to form the corresponding epoxy compound. Theabove-mentioned base is an inorganic base such as sodium hydroxide,sodium hydride, potassium t-butoxide or sodium carbonate, or an organicbase such as triethylamine, pyridine or DBU. The suitable solvent is anaqueous solvent or an organic solvent such as an alcohol, acetone, THFand DMF, and the reaction temperature is preferably in the range of 0°to 100° C. ##STR8## where R¹, R², A, E, F, G and H are as defined above,and X is a halogen atom. Afterward, the synthesized epoxy compound isthermally reacted with a corresponding amine derivative in a solvent inorder to obtain the compound having the general formula (I) wherein B is--CH₂ CH(OH)CH₂ -- of the present invention. ##STR9## where R¹, R², A,E, F, G and H are as defined above. As used above, "thermally" means inthe temperature range of from room temperature to a boiling point of theused solvent. The solvent is an organic solvent such as an alcohol,acetone, chloroform or DMF.

A second method of synthesizing the compounds of the present inventionis as follows: A halide such as epichlorohydrin or epibromohydrin isreacted with a corresponding amine derivative thermally or in thepresence of a base in a solvent in order to form the corresponding epoxycompound and hydroxyhalogen compound. ##STR10## where X is a halogen,and C and D are as defined above.

Afterward, a heterocyclic compound represented by the following formulais reacted with the above synthesized epoxy compound or hydroxyhalogencompound thermally or in the presence of a base or acid in a solvent inorder to obtain the compound having the general formula (I) wherein B is--CH₂ CH(OH)CH₂ -- of the present invention. ##STR11## where R¹, R², A,C, D, E, F, G and H are as defined above, and X is a halogen.

The above-mentioned base is an inorganic base such as sodium hydroxide,sodium hydride, potassium t-butoxide or potassium carbonate, or anorganic base such as triethylamine, pyridine or DBU. The above-mentionedacid is an organic acid such as tosyl or camphorsulfonic acid, aninorganic acid such as hydrochloric acid or sulfuric acid, or a Lewisacid such as titanium tetrachloride, tin tetrachloride ortrimethylsilyltrifluoromethanesulfonic acid. The solvent used is anorganic solvent such as methylene chloride, acetone, an alcohol,tetrahydrofuran or dimethylformamide. The term "thermally" means "in thetemperature range of from room temperature to a boiling point of thesolvent". A third method of synthesizing the compounds of the presentinvention is as follows: A heterocyclic compound represented by thefollowing formula is reacted with a dihalogenoalkyl material such as1,2-dibromoethane, 1,3-dibromopropane, 1,3-dichloropropane or1,4-dibromobutane in the presence of a base in a solvent in order toform the corresponding halogenoalkyl compound.

The above-mentioned base is an inorganic salt such as sodium hydroxide,sodium hydride, potassium t-butoxide or sodium carbonate, or an organicbase such as triethylamine, pyridine or DBU. The solvent used is anaqueous solvent or an organic solvent such as an alcohol, acetone, THFor DMF, and the reaction temperature is in the range of from roomtemperature to a boiling point of the used solvent. ##STR12## where R¹,R², A, E, F, G and H are as defined above, and X is a halogen atom.

Afterward, the synthesized halogenoalkyl compound is reacted with thecorresponding amine derivative thermally in a solvent, thereby obtaininga compound having the general formula (I) wherein B is --(CH₂)_(n) -- ofthe present invention. ##STR13## where R¹, R², A, C, D, E, F, G and Hare as defined above, and X is a halogen atom.

The above-mentioned "thermally" means in the temperature range of fromroom temperature to a boiling point of the used solvent. The solventused is an organic solvent such as an alcohol, acetone, chloroform orDMF. A fourth method of synthesizing compounds of the present inventionis as follows: A heterocyclic compound represented by the followingformula is reacted with an acid halide such as 3-chloropropionylchloride, or an acid anhydride thermally or in the presence of a base ina solvent, thereby forming the corresponding halide.

The above-mentioned "thermally" means in the temperature range of fromroom temperature to a boiling point of the used solvent.

The above-mentioned base is an inorganic base such as sodium hydroxide,sodium hydride or potassium t-butoxide, or an organic base such astriethylamine pyridine or DBU. The solvent used is a organic solventsuch as methylene chloride, chloroform or toluene. ##STR14## where R¹,R², A, E, F, G, H and X are as defined above.

Afterward, the synthesized halide is thermally reacted with acorresponding amine derivative in a solvent in order to obtain acompound having the general formula (I) wherein B is --CO(CH₂)_(n) -- ofthe present invention. ##STR15## where R¹, R², A, C, D, E, F, G, H and Xare as defined above.

The above-mentioned "thermally" means in the temperature range of fromroom temperature to a boiling point of the used solvent. The solventused is an organic solvent such as acetone, chloroform, an alcohol orDMF.

A fifth method of synthesizing compounds of the present invention is afollows: The hydroxyl group of the compound which has been obtained bythe first or second method is reacted with a corresponding acyl chlorideor the like, thereby preparing a compound having the general formula (I)wherein B is --CH₂ CH(OCOR³)CH₂ --. Alternatively, the above compound isreacted with p-toluenesulfonyl chloride or methanesulfonyl chloride, andthe resultant product is then reacted with an alkoxide of an alkalinemetal or an alkylamine to perform a substantial reaction, therebypreparing the compound of the general formula (I) wherein B is --CH₂CH(R⁴)CH₂ --. ##STR16## wherein R¹, R², A, C, D, E, F, G and H are asdefined above, R³ is hydrogen atom or a lower alkyl group, R⁴ is a loweralkoxy group, lower acyloxy group or lower alkylamino group, and Y is analkaline metal or hydrogen atom.

The present invention will now be described in detail with reference tothe following examples, but the scope of the present invention is not belimited to these examples.

The relative ability of the compounds of the present invention topotentiate the effect of anticancer drugs on drug-resistant cancer wasassessed by measuring the incorporation of anticancer drugs into cellsand by enforcement of therapeutic activity of anticancer drugs, using anadriamycin-resistant strain 2780AD of human ovarian cancer cells or anadriamycin-resistant strain K562/ADM of human myeloleukemia cells.Adriamycin is an anticancer drug.

The compounds according to the present invention manifest remarkablereinforcement activity in the incorporation of anticancer drugs andreinforcement activity in therapeutic effect of anticancer drugs, whichwill be explained in detail in the following Examples.

Anticancer drugs suitable for use in combination with the compounds orthe salts thereof according to the present invention are notspecifically limited: those preferably used are, for example,non-antimetabolites such as anthracycline group antibiotics, e.g.adriamycin, daunomycin or acrasinomycin A, actinomycin groupantibiotics, e.g. actinomycin C or actinomycin D, chromomycin groupantibiotics, e.g. mithramycin or toyomycin, vincalkaloids, e.g.vincristine or vinblastine, meitansins, podophyllotoxin derivatives,e.g. VP16-213, homoharintonin, angwindin, bruceantin, neocarbcinostatin,anthramycin, mitomycin C and cisplatin derivatives.

The compounds and the salts thereof according to the present inventioncan be administered independently with before or after theadministration of anticancer drugs or in combination with anticancerdrugs in the same delivered dosage unit. The compounds and their saltsaccording to the present invention can be administered as preparationssuited to various means of administration independently with variousanticancer drugs or, alternatively, can be administered as preparationsmixed with anticancer drugs. Modes of administration are naturallydifferent depending on the symptom(s) of patients to be treated.Physical form of anticancer drugs, etc. Amounts in the range between 1and 1,000 mg/day for an adult in a single or divided doses can be usedorally in forms such as tablets, granules, powders, suspensions,capsules or syrups, or as parental drugs such as injections,depositories or isotonic fluids for infusion.

For example, when prepared in tablet form, examples of absorbents to beused include crystallized cellulose and calcium silicate, and examplesof excipients are corn starch, lactose, calcium phosphate and magnesiumstearate among others. Furthermore, examples of injections be used arein a form of suspension in water or aqueous suspension with cotton seedoil, corn oil, peanut oil, olive oil, etc. or emulsion, for example,with compatible surfactants such as HCO-60. The anticancer drugs may beused as they are without modifications.

The compounds according to the present invention strongly suppress theoutflow of anticancer drugs from cancer cells and, moreover, arecharacterized by their low toxicity and extremely low incidence of sideeffects such as hypotonia.

The compounds according to the present invention are effective towardscancer cells, especially those less sensitive or resistant to anticancerdrugs, and can thus provide new therapeutic opportunities for thosepatients afflicted with such cancers and tumors.

The present invention is further illustrated by the following examples.

EXAMPLE 15-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline

(a) In 20 ml of dried DMF was dissolved 1 g of 5-hydroxyquinoline, and0.28 g of sodium hydride (60% content) was then added thereto, followedby heating with stirring at 50° C. for 30 minutes. Afterward, 1.92 g ofepichlorohydrin was further added to the reaction liquid and the latterwas then heated with stirring at 90° C. for 3 hours, and the solvent wasdistilled off under reduced pressure. Water was then added to theresidue, and the liquid was extracted with chloroform. The chloroformextract was then decolored and purified with active carbon, then wasdried with anhydrous sodium sulfate, and was distilled off. The residuewas then purified through a silica gel column chromatograph by the useof an effluent solvent of chloroform:methanol=100:1, so that 0.88 g of5-(2,3-epoxypropoxy)quinoline was obtained in an oily state.

(b) In 20 ml of ethanol were dissolved 0.88 g of the above obtainedepoxy compound and 1.1 g of N-diphenylmethylpiperazine, and the liquidwas then heated under reflux for 3 hours. After reaction, ethanol wasdistilled off, and the residue was then purified through a silica gelcolumn chromatograph, using chloroform:methanol=50:1 as an effluentsolvent. Afterward, fractions containing the desired compound werecombined. The solvent was then distilled off, and a small amount ofether was added to the residue for the purpose of crystallization.Afterward, the crystals were filtered and dried in order to obtain 1.5 gof 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline.

m.p.: 161°-163° C.

IR νcm⁻¹ (KBr): 3400(br), 2790, 1580, 1265, 1092, 788.

NMR δppm (CDCl₃): 2.3-2.9 (m,10H), 3.55 (br,s,1H), 4.05-4.25 (m,4H),6.82 (d,d,1H), 7.1-7.8 (m,13H), 8.54 (d,d,1H), 8.84 (d,d,1H).

EXAMPLE 25-[3-(4-(Dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

(a) With 80 ml of dioxane was mixed 11.3 g of anhydrous piperazine, and5.0 g of 5-chlorobenzosuberane was then added thereto. Afterward, thereaction liquid was heated under reflux for 7 hours. After cooling,insoluble substances were removed by filtration, and the solvent wasalso distilled off. A small amount of petroleum ether was added to theresidue for the purpose of crystallization, the crystals were collectedby filtration and were then dried, thereby obtaining 5.1 g ofN-(dibenzosuberane-5-yl)piperazine.

m.p.: 110°-111.5° C.

IR νcm⁻¹ (KBr): 3420, 3250, 2920, 2800, 1630, 1490, 1450, 1330, 1140.

(b) In 20 ml of ethanol were dissolved 0.88 g of the epoxy compoundobtained in the step (a) of Example 1 and 1.2 g ofN-(dibenzosuberane-5-yl)piperazine, and the liquid was then heated underreflux for 3 hours. After reaction, the solvent was distilled off, andthe residue was then purified through a silica gel column chromatograph.

A solvent of chloroform:methanol=50:1 was used as an effluent solvent,so that5-[3-(4-(dibenzosuberane-5-yl)-piperazine-1-yl)-2-hydroxypropoxy]quinolinewhich was the aimed compound was obtained in an amount of 1.4 g.

IR νcm⁻¹ (KBr): 2900, 2800, 1620, 1590, 1570, 1450, 1260, 1140, 1100.

NMR δppm (CDCl₃): 2.1-3.0 (m,12H), 3.1-3.6 (br,s,1H), 3.7-4.4 (m,6H),6.8 (d,1H), 6.9-7.9 (m,11H), 8.5 (d,1H), 8.8 (d,1H).

EXAMPLE 35-(3-[N-(2-(N-Diphenylmethyl-N-methylamino)ethyl)-N-methylamino]-2-hydroxypropoxy)quinoline

(a) In 100 ml of dioxane were dissolved 25 g ofN,N'-dimethylethylenediamine and 6 g of diphenylmethyl chloride, and theliquid was then heated under reflux for 4 hours. The solvent wasdistilled off, and water was then added to the residue, followed byextracting with chloroform.

The chloroform extract was then dried with anhydrous sodium sulfate, andthe solvent was distilled off.

The residue was then purified through a silica gel column chromatographby the use of a solvent of chloroform:methanol=25:1, thereby obtaining4.6 g of N-diphenylmethyl-N,N'-dimethylethylenediamine in an oily state.

IR νcm⁻¹ : 2960, 2860, 2800, 1600, 1500, 1460, 1030.

NMR δppm (CDCl₃): 1.8 (s,1H), 2.1 (s,3H), 2.35 (s,3H), 2.4-2.8 (m,4H),4.35 (s,1H), 7.1-7.6 (m,10H).

(b) In 20 ml of ethanol were dissolved 1.06 g of the above obtainedamine compound and the epoxy compound obtained in Example 1-(a), and theliquid was then heated under reflux for 3 hours. The solvent was thendistilled off under reduced pressure, and the residue was purifiedthrough a silica gel column chromatograph by the use of an effluent ofchloroform:methanol=100:1, thereby obtaining 1.3 g of5-(3-[N-(2-(N-diphenylmethyl-N-methylamino)ethyl)-N-methylamino]-2-hydroxypropoxy)quinoline.

IR νcm⁻¹ : 2960, 2800, 1620, 1590, 1580, 1490, 1450, 1280.

NMR δppm (CDCl₃): 2.2 (s,3H), 2.3 (s,3H), 2.4-3.0 (m,3H), 3.9-4.25(m,4H), 4.3 (s,1H), 6.9 (d,1H), 7.0-7.8 (m,13H), 8.5 (d,1H), 8.85(d,1H).

EXAMPLE 45-[3-(4-Diphenylmethylhomopiperazine-1-yl)-2-hydroxypropoxy]quinoline

In 20 ml of ethanol were dissolved 0.88 g of the epoxy compound obtainedin Example 1-(a) and 1.2 g of N-diphenylmethylhomopiperazine, and theliquid was then heated under reflux for 3 hours. After reaction, thesolvent was distilled off, and the residue was then purified through asilica gel column chromatograph. A solvent of chloroform:methanol=50:1was used as an effluent solvent, so that5-[3-(4-diphenylmethylhomopiperazine-1-yl)-2-hydroxypropoxy]quinolinewhich was intended therein was obtained in an amount of 1.6 g.

IR νcm⁻¹ (KBr): 3040, 3000, 2920, 2820, 1610, 1580, 1570, 1460, 1260,1170.

NMR δppm (CDCl₃): 1.8 (t,2H), 2.4-3.2 (m,10H), 3.65 (s,1H), 4.15 (s,3H),4.6 (s,1H), 6.8 (d,1H), 7.0-7.9 (m,13H), 8.5 (d,1H), 8.8 (d,1H).

EXAMPLE 52,4-Dimethyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline

(a) With 5.0 g of acetylacetone was mixed 2.8 g of3-amino-2-cyclohexenone, and the liquid was then heated with stirring at70° C. for 1 hour. The heating was further continued at a temperature of160° to 170° C. for 9 hours.

Excess acetylacetone and water were distilled off under reducedpressure, and the residue was then purified through a silica gel columnchromatograph by the use of an effluent of chloroform:methanol=50:1,thereby obtaining 1.85 g of2,4-dimethyl-5,6,7,8-tetrahydro-5-oxoquinoline.

m.p.: 54°-57° C.

(b) In 15 ml of diethylene glycol butylether acetate were dissolved 1.6g of the above synthesized tetrahydroquinoline compound and 0.2 g of 10%Pd-C, and the liquid was then heated with stirring at 200° C. for 6hours under a nitrogen gas stream.

After cooling, the deposited crystals were separated from Pd-C byfiltration, and the solvent was distilled off and the solvent-freefiltrate was then purified through a silica gel column chromatograph toobtain the desired product. Furthermore, the deposited crystals weredissolved in methanol, then filtered to remove Pd-C therefrom, andevaporated to dryness under reduced pressure, thereby obtaining thedesired compound, 2,4-dimethyl-5-hydroxyquinoline.

Total yield 0.82 g.

m.p.: 222°-224° C.

NMR δppm (DMSO-d₆): 2.50 (s,3H), 2.82 (s,3H), 6.7-7.1 (m,2H), 7.20-7 50(m,2H), 10.0 (s,1H).

(c) Following the same procedure as in Example 1-(a), 0.72 g of theabove synthesized hydroxyquinoline compound and epichlorohydrin weresubjected to reaction and treatment in order to form an epoxy compound.The latter was further reacted and treated with the diphenylpiperazinecompound in accordance with the same procedure as in Example 1-(b),thereby obtaining 1.13 g of2,4-dimethyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2800, 1600, 1450, 1260, 1050.

NMR δppm (CDCl₃): 2.5-2.85 (m,16H), 3.65 (br,s,1H), 4.0-4.3 (m,4H), 6.75(d,1H), 7.0 (s,1H), 7.15-7.6 (m,12H).

EXAMPLE 65-[3-(4-(6,11-Dihydrodibenzo[b,e]oxepine-11-yl)-piperazine-1-yl)-2-hydroxypropoxy]quinoline

(a) In 90 ml of dried ether was dissolved 4.05 g of6H-dibenzo[b,e]oxepine-11-one, and the liquid was then added dropwise,while being cooled with ice, to a solution in which LiAlH₄ was dispersedin 70 ml of dried ether.

The liquid was heated under reflux for 4.5 hours and was then cooled,and a saturated aqueous Glauber's salt solution was added thereto.

The liquid was filtered to remove insoluble substances therefrom,followed by drying. The solvent was then distilled off, and the residuewas purified through a silica gel column chromatograph by the use of aneffluent solvent of chloroform:methanol=100:1 in order to obtain 4.0 gof 11-hydroxy-6,11-dihydrodibenzo[b,e]oxepine.

IR νcm⁻¹ (KBr): 3260, 1600, 1570, 1480, 1440, 1280, 1250.

NMR δppm (CDCl₃): 1.55 (s,1H), 4.75-4.95 (m,1H),

5.3 (s,1H), 5.8-6.3 (m,1H), 6.5-7.6 (m,8H).

(b) In 70 ml of dried methylene chloride was dissolved 3.6 g of theabove obtained 11-hydroxydibenz[b,e]oxepine, and 3.0 g of thionylchloride was then added dropwise thereto under cooling with ice. Afterstirring at room temperature for 1 hour, the excessive solvent andthionyl chloride were distilled off under reduced pressure.

Furthermore, the residue was dissolved in 40 ml of methylene chloride,and the liquid was then added to a solution in which 8.8 g of anhydrouspiperazine was dissolved in 90 ml of methylene chloride, followed bystirring at room temperature for 1 hour.

Insoluble substances were removed therefrom by filtration, and thefiltrate was washed with water and was then dried.

After the solvent was distilled off, the liquid was purified with asilica gel column chromatograph, using an effluent solvent ofchloroform:methanol=20:1, in order to obtain 3.2 g of11-piperazino-6,11-dihydrodibenzo[b,e]-oxepine.

NMR δppm (CDCl₃): 2.1 (s,1H), 2.2-3.0 (m,8H), 3.8 (s,1H), 4.6 (d,1H),6.7 (s,1H), 6.8-7.3 (m,8H).

(c) Following the same procedure as in Example 1-(b), 2.5 g of the abovesynthesized dizenzooxepine compound and 1.1 g of the epoxy compoundsynthesized in Example 1-(a) were subjected to reaction and treatment,thereby obtaining 2.6 g of5-[3-(4-(6,11-dihydrodibenzo[b,e]oxepine-11-yl)-piperazine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2930, 2800, 1615, 1590, 1570, 1480, 1450, 1270.

NMR δppm (CDCl₃): 2.1-3.0 (m,10H), 3.9 (s,1H), 4.05-4.3 (m,3H), 4.7(d,1H), 6.8 (t,4H), 7.0-7.4 (m,8H), 7.55 (t,1H), 7.7 (d,1H), 8.55(d,1H), 8.55 (d,1H).

EXAMPLE 75-[3-(4-(Diphenyl-hydroxymethyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline

Reaction and treatment were carried out using 0.4 g of the epoxycompound synthesized in Example 1-(a) and 0.6 g of-(diphenyl-hydroxymethyl)piperidine in accordance with the sameprocedure as in Example 1-(b), in order to obtain 0.75 g of5-[3-(4-(diphenyl-hydroxymethyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3380, 2925, 1610, 1580, 1568, 1265 1095, 790, 740, 695.

NMR δppm (CDCl₃): 1.55 (m,4H), 2.09 (m,1H), 2.3-2.5 (m,2H), 2.5-2.7(m,2H), 2.95 (m,1H), 3.09 (m,1H), 3.6 (br,2H), 4.0-4.25 (m,3H), 6.80(d,1H), 7.15 (m,2H), 7.2-7.35 (m,5H), 7.4-7.6 (m,5H), 7.66 (d,1H), 8.53(dd,1H), 8.81 (dd,1H).

EXAMPLE 85-[3-(4-(2,2-Diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]-2-methoxyquinoline

(a) Reaction and treatment were carried out using 1.6 g of5-hydroxy-2-methoxyquinoline in accordance with the same procedure as inExample 1-(a), in order to obtain5-(2,3-epoxypropoxy)-2-methoxyquinoline.

NMR δppm (CDCl₃): 2.82 (dd,1H), 2.95 (t,1H), 3.4-3.5 (m,1H), 4.0-4.2(m,1H), 4.06 (s,3H), 4.38 (dd,1H), 6.71 (dd,1H), 6.86 (d,1H), 7.4-7.55(m,2H), 8.42 (d,1H).

(b) Reaction and treatment were carried out using 0.7 g of the abovesynthesized epoxy compound and 1.0 g of N-(2,2-diphenylacetyl)piperazinein accordance with the same procedure as in Example 1-(b), in order toobtain 1.39 g of5-[3-(4-(2,2-diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]-2-methoxyquinoline.

IR νcm⁻¹ (KBr): 1630, 1610, 1590, 1570, 1430, 1395, 1310, 1240.

NMR δppm (CDCl₃): 2.2-2.8 (m,6H), 3.4-3.6 (m,2H), 3.6-3.9 (m,2H),3.9-4.3 (m,6H), 5.19 (s,1H), 6.6-6.75 (m,1H), 6.85 (d,1H), 7.0-7.6(m,14H), 8.34 (d,1H).

EXAMPLE 95-[3-(4-(Dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]-2-methoxyquinoline

Reaction and treatment were carried out using 0.7 g of the epoxycompound synthesized in Example 8-(a) and 0.92 g of thedibenzosuberanylpiperazine compound synthesized in Example 2-(a), inorder to obtain 1.22 g of the desired compound.

IR νcm⁻¹ (KBr): 3040, 3000, 2920, 2800, 1610, 1595, 1570, 1430, 1395,1310, 1200.

NMR δppm (CDCl₃): 2.2-2.9 (m,12H), 3.9-4.2 (m,6H), 4.05 (s,3H), 6.71(dd,1H), 6.84 (d,1H), 7.0-7.3 (m,8H), 7.4-7.52 (m,2H), 8.37 (d,1H).

EXAMPLE 105-(3-[N-(2-(N-Diphenylmethyl-N-ethylamino)ethyl)-N-ethylamino]-2-hydroxypropoxy)quinoline

(a) Reaction and treatment were carried out using 21 g ofN,N'-diethylethylenediamine and 7.3 g of diphenylmethyl chloride inaccordance with the same procedure as in Example 3-(a), in order toobtain 4.2 g of N-diphenylmethyl-N,N'-diethylethylenediamine.

NMR δppm (CDCl₃): 0.9-1.4 (m,6H), 2.4-3.2 (m,8H), 4.8 (s,1H), 7.1-7.8(m,10H)

(b) Reaction and treatment were carried out using 1.52 g of the abovesynthesized diamine compound and 1.08 g of the epoxy compoundsynthesized in Example 1-(a) in accordance with the same procedure as inExample 1-(b), in order to obtain 0.5 g of5-(3-[N-(2-(N-diphenylmethyl-N-ethylamino)ethyl)-N-ethylamino]-2-hydroxypropoxy)quinoline.

IR νcm⁻¹ (KBr): 3400, 1630, 1590, 1450, 1410, 1280, 1100.

NMR δppm (CDCl₃): 1.0 (m,6H), 2.3-2.9 (m,10H), 3.95-4.2 (m,4H), 6.85(d,1H), 7.0-7.85 (m,11H), 8.55 (d,1H), 8.9 (d,1H).

EXAMPLE 115-[3-(4-(2,3,3',4'-Tetramethoxydiphenylmethyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

(a) Following the same procedure as in Example 6-(b), reaction andtreatment were carried out using 3.45 g of2,3,3',4'-tetramethoxybenzohydrol in order to obtain 3.1 g ofN-(2,3,3',4'-tetramethoxydiphenylmethyl)piperazine.

NMR δppm (CDCl₃): 1.9 (s,1H), 2.35 (s,4H), 2.85 (t,4H), 3.8 (s,12H), 4.7(s,1H), 6.75 (m,2H), 7.0 (m,3H), 7.25 (s,1H).

(b) Following the same procedure as in Example 1-(b), reaction andtreatment were carried out using 3.1 g of the above synthesizedpiperazine derivative and 0.86 g of the epoxy compound synthesized inExample 1-(a), in order to obtain 1.82 g of5-[3-(4-(2,3,3',4'-tetramethoxydiphenylmethyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2920, 1640, 1595, 1520, 1480, 1420, 1280.

NMR δppm (CDCl₃): 1.8-2.3 (m, 1H), 2.3-2.9 (m,10H), 3.5-4.0 (s,12H),4.05-4.4 (m,3H), 4.7 (s,1H), 6.75 (q,2H), 6.85 (d,1H), 6.95-7.1 (m,3H),7.25 (s,1H), 7.35 (q.1H), 7.55 (t,1H), 7.7 (d,1H), 8.55 (d,1H), 8.9(q,1H).

EXAMPLE 123-Ethyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline

In 10 ml of DMF was dissolved 750 mg of 3-ethyl-5-hydroxy quinoline, and180 mg of 60% sodium hydride was then added thereto. The solution wasstirred at 50° C. for 30 minutes, and 1.25 g of epichlorohydrin was thenadded thereto, followed by stirring at 90° C. for 3 hours. Afterward,the solvent was distilled off, and the residue was dissolved inchloroform and was then washed with water. The chloroform layer wasdried and concentrated, and this residue was dissolved in 10 ml ofethanol. Furthermore, 750 mg of N-diphenylmethylpiperazine was addedthereto, and the liquid was then heated under reflux for 3 hours.

The solvent was then distilled off, and the residue was purified througha silica gel column chromatograph by the use of an effluent solvent ofchloroform:methanol=50:1, thereby obtaining 800 mg of3-ethyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3450, 2805, 1600, 1578, 1450, 1262, 1090, 742, 705.

NMR δppm (CDCl₃): 1.32 (t,3H), 2.3-2.85 (m,12H), 4.0-4.25 (m,4H), 6.80(d,1H), 7.1-7.28 (m,6H), 7.37-7.5 (m,5H), 7.64 (d,1H), 8.28 (d,1H), 8.73(d,1H).

EXAMPLE 135-[3-(4-(Diphenylmethylene)piperidine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 1.25 g of 4-(diphenylmethylene)piperidine,thereby obtaining 0.96 g of the desired compound.

NMR δppm (CDCl₃): 2.3-3.0 (m,10H), 4.1-4.4 (m,3H), 6.87 (d,1H), 7.0-7.5(m,11H), 7.5-7.8 (m,2H), 8.5-8.75 (m,1H), 8.75-9.0 (m,1H).

EXAMPLE 145-[3-(4-(Diphenylmethyl)piperidine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 1.09 g of 4-(diphenylmethyl)piperidine, therebyobtaining 0.14 g of the desired compound.

NMR δppm (CDCl₃ +DMSO-d₆): 1.6-1.9 (m,4H), 2.3-2.5 (m,1H), 2.5-2.7(m,3H), 2.7-3.0 (m,1H), 3.0-3.3 (m,1H), 3.3-3.7 (m,3H), 4.1-4.3 (m,2H),4.55-4.75 (m,1H), 6.83-6.94 (m,1H), 7.68-7.70 (m,13H), 8.6-8.7 (m,1H),8.84-8.92 (m,1H).

EXAMPLE 155-[2-Hydroxy-3-(4-(phenyl-2-pyridylmethyl)piperazine-1-yl)propoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.93 g of N-(phenyl-2-pyridylmethyl)piperazine toobtain 1.22 g of the desired compound.

NMR δppm (CDCl₃): 1.57 (s,1H), 2.3-2.9 (m,10H), 4.05-4.30 (m,3H), 4.45(s,1H), 6.87 (d,1H), 7.05-7.72 (m,12H), 8.52 (d,1H), 8.58 (d,1H), 8.90(dd,1H).

EXAMPLE 165-[3-(4-(2,2-Diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.85 g of the epoxy compound synthesized inExample 1-(a) and 1.12 g of N-(2,2-diphenylacetyl)piperazine to obtain1.2 g of the desired compound.

NMR δppm (CDCl₃): 2.1-2.3 (m,1H), 2.3-2.75 (m,5H), 3.3-3.6 (m,3H),3.6-3.8 (m,2H), 4.05-4.25 (m,3H), 5.18 (s,1H), 6.83 (d,1H, 7.1-7.45(m,11H), 7.57 (t,1H), 7.69 (d,1H), 8.4-8.55 (m,1H).

EXAMPLE 175-[3-(4-(2,2-Diphenylethyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.85 g of the epoxy compound synthesized inExample 1-(a) and 1.07 g of N-(2,2-diphenylethyl)piperazine to obtain1.2 g of the desired compound.

NMR δppm (CDCl₃): 2.3-2.75 (m,10H), 2.97 (d,2H), 4.0-4.25 (m,4H), 6.85(d,1H), 7.10-7.70 (m,13H), 8.45-8.55 (m,1H), 8.80-8.92 (m,1H).

EXAMPLE 185-[3-(4-(5-Dibenzosuberanyl)piperazine-1-yl)-2-hydroxypropoxy]-2-chloroquinoline

(a) Following the same procedure as in Example 1-(a), reaction andtreatment were carried out using 0.8 g of 2-chloro-5-hydroxyquinoline toobtain 0.62 g of 2-chloro-5-(2,3-epoxypropoxy)quinoline.

IR νcm⁻¹ (KBr): 3040, 2980, 2820, 1610, 1580, 1490, 60, 1395, 1370,1290, 1260, 1200, 1170, 1140, 30, 1075, 1060, 900, 860, 820, 790, 740.

(b) Following the same procedure as in Example 1-(b), reaction andtreatment were carried out using 0.32 g of the above synthesized epoxycompound and 0.37 g of N-(dibenzosuberanyl)piperazine synthesized inExample 2-(a), in order to obtain 0.63 g of5-[3-(4-(dibenzosuberanyl)piperazine-1-yl)-2-hydroxypropoxy]-2-chloroquinoline.

NMR δppm (CDCl₃): 2.15-2.9 (m,12H), 3.9-4.25 (m,6H), 6.75-6.95 (m,1H),6.95-7.40 (m,9H), 7.58 (d,1H9, 8.47 (d,1H).

EXAMPLE 195-[3-(4-(Diphenyl-hydroxymethyl)piperidine-1-yl)-2-hydroxypropoxy]-2-chloroquinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.31 g of the epoxy compound synthesized inExample 18-(a) and 0.35 g of 4-(diphenyl-hydroxymethyl)piperidine toobtain 0.52 g of the desired compound.

NMR δppm (CDCl₃): 1.35-1.6 (m,4H), 1.95-2.7 (m,6H), 2.8-3.0 (m,1H),3.0-3.2 (m,1H), 4.0-4.25 (m,3H), 6.8-6.9 (m,1H), 7.1-7.65 (m,13H), 8.48(d,1H).

EXAMPLE 205-[3-(4-(5-Dibenzosuberenyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.4 g of the epoxy compound synthesized inExample 1-(a) and 0.6 g of N-(dibenzosuberenyl)piperazine to obtain 0.85g of the desired compound.

NMR δppm (CDCl₃): 1.9-2.7 (m,10H), 4.0-4.25 (m,3H), 4.29 (s,1H), 6.82(d,1H), 6.96 (s,2H), 7.15-7.80 (m,11H), 8.40-8.50 (m,1H), 8.80-8.90(m,1H).

EXAMPLE 212,4-Dimethyl-5-[3-(4-(6,11-dihydrodibenzo[b,e]oxepine-11-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 5-(c), reaction and treatmentwere carried out using 0.8 g of 2,4-dimethyl-5-hydroxyquinoline preparedin Example 5-(b) and 1.04 g of11-piperazino-6,11-dihydro-dibenzo[b,e]oxepine prepared in Example6-(b), in order to obtain 1.6 g of the desired compound.

IR νcm⁻¹ (KBr): 3400, 1630, 1594, 1440, 1380, 1260.

NMR δppm (CDCl₃): 2.25-2.6 (m,10H), 2.6 (s,3H), 2.85 (s,3H), 3.9 (s,1H),4.05-4.25 (m,3H), 4.7 (d,1H), 6.8 (m,4H), 6.95 (s,1H), 7.05-7.35 (m,6H),7.5 (t,1H), 7.6 (d,1H).

EXAMPLE 225-[3-(4-(Dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]-2,4-dimethylquinoline

Following the same procedure as in Example 5-(c), reaction and treatmentwere carried out using 0.8 g of 2,4-dimethyl-5-hyroxyquilone synthesizedin Example 5-(b) and 1.04 g of dibenzosuberanylpiperazine synthesized inExample 2-(a), in order to obtain 1.6 g of the desired compound.

NMR δppm (CDCl₃): 2.2-2.9 (m,12H), 2.62 (s,3H), 2.83 (s,3H), 3.9-4.25(m,6H), 6.75 (d,1H), 6 95-7.25 (m,9H), 7.48 (t,1H), 7.59 (d,1H).

EXAMPLE 235-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-6-methylquinoline

(a) In 20 ml of a 80% aqueous sulfuric acid solution were dissolved 3.48g of 3-amino-6-methylphenol, 5.5 ml of glycerol and 7 g of sodiumm-nitrobenzene sulfonate, and the liquid was then heated with stirringat 150° C. for 1 hour.

After cooling, the liquid was neutralized with an aqueous sodiumhydroxide solution to a pH of 8 to 9.

The resulting aqueous layer was removed therefrom by filtration, and theresidue was then dissolved in methanol and insoluble substances wereafterward filtered off.

The methanol solution was concentrated and then purified through asilica gel column chromatograph by the use of an effluent solvent ofchloroform:methanol=25:1, thereby obtaining 0.17 g of5-hydroxy-6-methylquinoline and 1.6 g of 7-hydroxy-6-methylquinoline.

5-Hydroxy-6-methylquinoline

IR νcm⁻¹ (KBr): 1578, 1255, 1178, 1082, 915, 800.

NMR δppm (CMSO-d₆): 2.4 (s,3H), 7.42 (dd,1H), 7.5 (s,1H), 8.62 (dd,1H),8.78 (dd,1H), 9.3 (br,1H).

7-Hydroxy-6-methylquinoline

NMR δppm (CMSO-d₆): 2.38 (s,3H), 7.31 (dd,1H), 7.4 (s,1H), 7.7 (s,1H),8.20 (dd,1H), 8.72 (dd,1H).

(b) In 50 ml of acetone were dissolved 5.04 g ofdiphenylmethylpiperazine and 5.5 g of epichlorohydrin, and 4.2 ml oftriethylamine was then added thereto.

The liquid was heated under reflux for 2 hours, and the solvent was thendistilled off under reduced pressure. The residue was purified by asilica gel column chromatograph to obtain 2.9 g of4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine and 2.8 g of4-(2,3-epoxypropyl)-1-diphenylmethylpiperazine.

4-(3-Chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine

NMR δppm (CDCl₃): 2.2-2.9 (m,10H), 3.5-4.0 (m,3H), 4.20 (s,1H), 7.0-7.5(m,10H).

4-(2,3-Epoxypropyl)-1-diphenylmethylpiperazine

NMR δppm (CDCl₃): 2.1-2.8 (m,12H), 2.9-3.1 (m,1H), 4.20 (s,1H), 7.0-7.5(m,10H).

(c) In 10 ml of dried THF were dissolved 170 mg of5-hydroxy-6-methylquinoline synthesized in the preceding step (a) and395 mg of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazinesynthesized in the preceding step (b), and 143 mg of t-BuOK was thenadded thereto.

Afterward, the liquid was heated under reflux for 10 hours and was thenpoured into an aqueous ammonium chloride solution, and it was thenextracted with chloroform. The extract was dried with anhydrousmagnesium sulfate and then concentrated.

The residue was purified through a silica gel column chromatograph bythe use of an effluent solvent of chloroform:methanol=50:1, therebyobtaining 100 mg of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-6-methylquinoline.

NMR δppm (CDCl₃): 3.46 (s,3H), 2.2-3.0 (m,10H), 3.7 (br,s,1H), 3.8-4.1(m,2H), 4.0-4.2 (m,1H), 4.23 (s,1H), 7.7-7.0 (m,12H), 7.88 (d,1H), 8.60(dd,1H), 8.86 (dd,1H).

EXAMPLE 245-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-methylquinoline

(a) Following the same procedure as in Example 23-(a), reaction andtreatment were carried out using 3.9 g of 3-amino-4-methylphenol, 7 mlof glycerol, 8.7 g of sodium m-nitrobezene sulfonate and 29 ml of a 80%aqueous sulfuric acid solution in order to obtain 290 mg of 5-hydroxy-8-methylquinoline.

NMR δppm (DMSO-d₆): 6.8 (d,1H), 7.3 (d,1H), 7.3 (dd,1H), 8.5 (dd,1H),7.8 (dd,1H), 10.0 (br,s,1H).

(b) Following the same procedure as in Example 23-(c), reaction andtreatment were carried out using 360 mg of the above synthesized5-hydroxy-8-methylquinoline, 1.39 g of4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine and mg of t-BuOKin order to obtain 120 mg of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-methylquinoline.

IR νcm⁻¹ (KBr): 3350, 2900, 1610, 1580, 1540, 1430, 1360, 1270, 1230,1200, 1080, 900, 800, 740, 690.

NMR δppm (CDCl₃): 2.4-2.7 (m,10H), 3.79 (br,s,1H), 4.0-4.2 (m,3H), 4.2(s,1H), 6.7 (d,1H), 7.1-7.4 (m,12H), 8.5 (dd,1H), 8.9 (dd.1H).

EXAMPLE 255-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-methoxyquinoline

(a) Following the same procedure as in Example 23-(a), reaction andtreatment were carried out using 2.25 g of 3-amino-4-methoxyphenol, 3.7ml of glycerol and sodium m-nitrobenzene sulfonate to obtain 180 mg of5-hydroxy-8-methoxyquinoline.

NMR δppm (CDCl₃ +DMSO-d₆): 4.0 (s,3H), 6.90 (s,2H), 7.41 (dd,1H), 8.58(dd,1H), 8.90 (dd,1H), 9.30 (br,1H).

(b) Following the same procedure as in Example 23-(c), reaction andtreatment were carried out using 180 mg of 5-hydroxy-8-methoxyquinolineto obtain 140 mg of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxy-propoxy]-8-methoxyquinoline.

IR νcm⁻¹ (KBr): 3360, 2500, 1620, 1580, 1540, 1470, 1440, 1400, 1370,1280, 1100, 900, 800, 730.

NMR δppm (CDCl₃): 2.5-2.8 (m,10H), 3.28 (br,s,1H), 4.03 (s,3H), 4.0-4.2(m,2H), 4.24 (s,1H), 6.77 (d,1H), 6.90 (d,1H), 7.15-7.45 (m,11H), 8.54(dd,1H), 8.93 (dd,1H).

EXAMPLE 265-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-nitroquinoline

Following the same procedure as in Example 23-(c), reaction andtreatment were carried out using 180 mg of 5-hydroxy-8-nitroquinoline toobtain 15 mg of the desired compound.

IR νcm⁻¹ (KBr): 3350, 2900, 2400, 1610, 1570, 1510, 1420, 1310, 1270,1180, 1080, 1000, 900, 730.

NMR δppm (CDCl₃): 2.5-2.9 (m,10H), 4.2-4.3 (m,4H), 6.7 (d,1H), 7.1-7.4(m,11H), 8.2 (d,1H), 8.7 (dd,1H), 9.1 (dd,1H).

EXAMPLE 275-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropylamino]quinoline

In 20 ml of chloroform were dissolved 1.11 g of 5-aminoquinoline and1.19 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine, andthe liquid was then heated at a temperature of 180° to 200° C. for 4hours in an autoclave.

The reaction liquid was then concentrated, and the residue was purifiedthrough a silica gel column chromatograph by the use of ethyl acetate asan effluent solvent, thereby obtaining 460 mg of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxy-propylamino]quinoline.

IR νcm⁻¹ (KBr): 3220, 2500, 1620, 1570, 1510, 1410, 1330, 1290, 1010.

NMR δppm (CDCl₃): 2.2-2.8 (m,10H), 3.1-3.5 (m,2H), 3.6 (br,1H), 4.0-4.2(m,1H), 4.21 (s,1H), 5.1 (br,1H), 6.57 (d,1H), 7.1-7.5 (m,12H), 8.25(d,1H), 8.84 (d,1H).

EXAMPLE 285-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropylamino]-8-methoxyquinoline

Following the same procedure as in Example 27, reaction and treatmentwere carried out using 1.81 g of 5-amino-8-methoxyquinoline and 1.23 gof 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine to obtain 200mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxy-propylamino]-8-methoxyquinoline.

IR νcm⁻¹ (KBr): 3350, 2900, 2780, 1600, 1580, 1470, 1440, 1390, 1270,1090, 990, 730, 690.

NMR δppm (CDCl₃): 2.4-2.7 (m,10H), 3.09 (dd,1H), 3.30 (dd,1H), 4.0(s,3H), 40-4.2 (m,1H), 4.22 (s,1H), 4.5 (br,1H), 6.54 (d,1H), 6.92(d,1H), 7.1-7.4 (m,11H), 8.25 (dd,1H), 8.90 (dd,1H).

EXAMPLE 295-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-chloroquinoline

Following the same procedure as in Example 23-(c), reaction andtreatment were carried out using 0.64 g of 8-chloro-5-hydroxyquinolineand 1.48 g of 4-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazinesynthesized in Example 23-(b), in order to obtain 0.68 g of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-chloroquinoline.

IR νcm⁻¹ (KBr): 3400, 2920, 2800, 1600, 1580, 1300, 1250, 1150, 1080,1000.

NMR δppm (CDCl₃): 2.1-3.3 (m,10H), 4.0-4.2 (m,4H), 4.22 (s,1H), 6.70(d,1H), 7.07-7.45 (m,11H), 7.67 (d,1H), 8.58 (dd,1H), 9.02 (dd,1H).

EXAMPLE 30N-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropyl]-N-methyl-5-quinolineamine

(a) With 7.2 g of 5-aminoquinoline was mixed 40 ml of ethylorthoformate, and the liquid was then heated under reflux for 5 hours.An excessive amount of ethyl orthoformate was distilled off, and theresidue was then dissolved in 250 ml of anhydrous ethanol. Afterward,3.8 g of sodium boron hydride was added thereto under cooling with ice.The liquid was allowed to stand at room temperature overnight, and itwas then heated at a temperature of 40° to 50° C. for 2 hours.

Afterward, the solvent was distilled off under reduced pressure, andwater was then added to the liquid. The latter was extracted withmethylene chloride, and the - extract was then dried with anhydrousGlauber's salt. The solvent was distilled off, and the residue was thenwashed with ether to obtain 3.3 g of 5-(methylamino)quinoline.

NMR δppm (CDCl₃): 3.05 (d,3H), 4.4 (dr,1H), 6.6 (dd,1H), 7.1-7.7 (m,3H),8.2 (dd,1H), 8.8 (dd,1H).

(b) In 15 ml of THF was dissolved 0.59 g of the above synthesized5-(methylamino)quinoline, and 2.36 ml of a 1.6 M n-BuLi hexane solutionwas added thereto under cooling with ice. Next, a solution was addedthereto which had been prepared by dissolving 1.42 g of4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine in 8 ml of THF.Furthermore, 2.36 ml of a 1.6 M n-BuLi hexane solution was addedthereto, and the liquid was then allowed to stand at room temperatureovernight. The reaction liquid was added to an aqueous ammonium chloridesolution and was then extracted with methylene chloride.

The extract was dried with anhydrous magnesium sulfate and was thenconcentrated, and the residue was purified through a silica gel columnchromatograph by the use of a effluent solvent of methylenechloride:methanol=20:1, thereby obtaining 230 m ofN-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropyl]-N-methyl-5-quinolineamine.

IR νcm⁻¹ (KBr): 3400, 2600, 1630, 1590, 1450, 1410.

NMR δppm (CDCl₃): 2.1-2.6 (m,6H), 2.90 (s,3H), 3.00 (dd,1H), 3.19(dd,1H), 3.59 (br,s,1H), 3.95-4 03 (m,1H), 4.20 (s,1H), 7.0-7.5 (m,12H),7.58 (dd,1H), 7.85 (d,1H), 8.69 (d,1H), 8.86 (d,1H).

EXAMPLE 315-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxy-propylthio]quinoline

Following the same procedure as in Example 23-(c), reaction andtreatment were carried out using 220 mg of 5-quinolinethiol and 1.2 g of4-(3-chloro-2-hydroxypropyl)-1-(diphenylmethyl)piperazine, in order toobtain 130 mg of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropylthio]quinoline.

NMR δppm (CDCl₃): 2.2-2.7 (m,10H), 3.0-3.1 (m,2H), 3.9 (m,1H), 4.20(s,1H), 7.1-7.8 (m,13H), 8.00 (d,1H), 8.75 (d,1H), 8.93 (d,1H).

EXAMPLE 32 5-[3-(4-Diphenylmethylpiperazine-1-yl)propoxy]quinoline

(a) Following the same procedure as in Example 1-(a), reaction andtreatment were carried out using 1.0 g of 5-hyroxyquinoline, 2.1 g of1,3-dibromopropane and 0.78 g of t-BuOK as a base, in order to obtain0.65 g of 5-(3-bromopropoxy)quinoline.

(b) Following the same procedure as in Example 1-(b), reaction andtreatment were carried out using 0.65 g of the above synthesizedbromo-compound and 0.62 g of N-diphenylmethylpiperazine, in order toobtain 0.65 g of5-[3-(4-diphenylmethylpiperazine-1-yl)propoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 1600, 1450, 1420, 1380, 1280, 1100.

NMR δppm (CDCl₃) 2.0-2.15 (t,2H), 2.3-2.7 (m,10H), 4.15 (t,2H), 4.23(s,1H), 6.81 (d,1H), 7.16-7.7 (m,13H), 8.55 (d,1H), 8.88 (d,1H).

EXAMPLE 33 5-[4-(4-Diphenylmethylpiperazine-1-yl)butoxy]quinoline

Following the same procedure as in Example 32-(a), reaction andtreatment were carried out using 1.0 g of 5-hydroxyquinoline and 2.3 gof 1,4-dibromobutane to obtain 0.78 g of 5-(4-bromobutoxy)quinoline.Furthermore, the same procedure as in Example 32-(b) was repeated withthe exception that 0.78 g of N-diphenylmethylpiperazine was used, inorder to perform reaction and treatment, so that 0.8 g of the desiredcompound was obtained.

IR νcm⁻¹ (KBr): 3420, 1635, 1595, 1415, 1280.

NMR δppm (CDCl₃): 1.7-2.1 (m,4H), 2.3-2.8 (m,10H), 4.1-4.3 (m,3H), 6.8(d,1H), 7.1-7.8 (m,13H), 8.55 (d,1H), 8.9 (d,1H).

EXAMPLE 34 5-[2-(4-Diphenylmethylpiperazine-1-yl)ethoxy]quinoline

Following the same procedure as in Example 32-(a), reaction andtreatment were carried out using 1.05 g of 5-hydroxyquinoline and 2.04 gof 1,2-dibromoethane to obtain 0.2 g of 5-(2-bromoethoxy)quinoline.

Furthermore, the same procedure as in Example 32-(b) was repeated withthe exception that 0.2 g of N-diphenylmethylpiperazine was used, toperform reaction and treatment, so that 0.1 g of the desired compoundwas obtained. NMR δppm (CDCl₃): 2.4-3.2 (m,10H), 4.2-4.5 (m,3H), 6.85(d,1H), 7.1-7.8 (m,13H), 8.5 (d,1H), 8.9 (d,1H).

EXAMPLE 35 5-[3-(4-Diphenylmethypiperazine-1-yl)propionamido]quinoline

(a) In 60 ml of methylene chloride was dissolved 4.5 g of5-aminoquinoline, and 10.5 g of 3-chloropropionyl chloride and 9 g oftriethylamine were then added thereto. After the liquid was allowed tostand at room temperature overnight, a 1 N aqueous sodium hydroxidesolution was added to the liquid, and the latter was then extracted withmethylene chloride. The extract was washed twice with an aqueous sodiumbicarbonate solution, was then dried, and was concentrated to obtaincrystals. The latter were washed with methylene chloride, and filteredto obtain 2.2 g of 5-(3-chloropropionamido)quinoline in a crystallinestate.

NMR δppm (CDCl₃): 2.9 (t,2H), 3.3 (s,1H), 3.9 (t,2H), 7.0-8.5 (m,5H),8.9 (dd,1H).

(b) Following the same procedure as in Example 1-(b), 1.1 g of the abovesynthesized chloro-compound and 1.2 g of N-diphenylmethylpiperazinesynthesized in Example 1-(b) were reacted and treated in an ethanolsolvent to obtain 1.0 g of5-[3-(4-diphenylmethylpiperazine-1-yl)propionamide)]quinoline.

IR νcm⁻¹ (KBr): 3420, 2580, 1690, 1630, 1600, 1550, 1420, 1370, 1280.

NMR δppm (CDCl₃): 2.4-3.9 (m,12H), 4.29 (s,1H), 7.1-7.5 (m,11H), 7.69(t,1H), 7.88 (d,1H), 8.21 (d,1H), 8.35 (d,1H), 8.92 (d,1H), 11.09(s,1H).

EXAMPLE 365-[3-(4-Dibenzosuberane-5-yl)piperazine-1-yl)propionamido]quinoline

Following the same procedure as in Example 1-(b), 1.1 g of thechloro-compound synthesized in Example 35-(a) and 1.32 g ofN-(dibenzosuberane-5-yl)piperazine synthesized in Example 2-(a) werereacted and treated in an ethanol solvent to obtain 1 6 g of5-[3-(4-dibenzosuberanylpiperazine-1-yl)propion-amido]quinoline.

IR νcm⁻¹ (KBr): 3400, 2620, 1690, 1630, 1590, 1530, 1410, 1280.

NMR δppm (CDCl₃): 2.2-3.0 (m,14H), 3.9-4.1 (m,3H), 7.0-7.2 (m,8H), 7.50(dd,1H), 7.73 (t,1H), 7.92 (d,1H), 8.20 (d,1H), 8.46 (d,1H), 9.01(d,1H), 11.1 (s,1H).

EXAMPLE 375-[N-Methyl-(3-(4-diphenylmethylpiperazine-1-yl)propionamido)]quinoline

In 30 ml of methylene chloride was dissolved 474 mg of5-(methylamino)quinoline synthesized in Example 30-(a), and 850 mg of3-chloropropionyl chloride and 0.5 ml of triethylamine were addedthereto at room temperature. After standing at room temperatureovernight, a 1 N aqueous sodium hydroxide solution was then added to theliquid so as to alkalinize it. The alkaline liquid was extracted withmethylene chloride, and the extract was then washed twice with anaqueous sodium bicarbonate solution and dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and 756mg of N-(diphenylmethyl)piperazine was added to the residue. The liquidwas reacted and treated in an ethanol solvent in accordance with thesame procedure as in Example 1-(b) to obtain 880 mg of5-[N-methyl-(3-(4-diphenylmethylpiperazine-1-yl)propionamido)]quinoline.

IR νcm⁻¹ (KBr): 3400, 2520, 1650, 1500, 1410, 1120.

NMR δppm (CDCl₃): 1.9-2.50 (m,10H), 2.64 (br,t,2H), 3.34 (s,3H), 4.13(s,1H), 7.0-7.5 (m,12H), 7.72 (dd,1H), 8.1-8.2 (m,2H), 8.97 (dd,1H).

EXAMPLE 385-[N-Methyl-(3-(4-dibenzosuberane-5-yl)propionamide)]-quinoline

Following the same procedure as in Example 37, 474 mg of5-(methylamino)quinoline was reacted with 850 mg of 3-chloropropionylchloride. The reaction product was reacted and treated with 834 mg ofN-(dibenzosuberane-5-yl)piperazine synthesized in Example 2-(a) in anethanol solvent in accordance with the same procedure as in Example2-(a), in order to obtain 1.02 g of5-[N-methyl-(3-(4-dibenzosuberanylpiperazine-1-yl)-propionamide)]quinoline.

IR νcm⁻¹ (KBr): 3400, 2900, 2500, 1650, 1590, 1410, 1120.

NMR δppm (CDCl₃): 1.7 (br,1H), 1.8-2.4 (m,12H), 2.5-2.6 (m,2H), 2.6-2.9(m,2H), 3.34 (s,3H), 3.86 (s,1H), 3.8-4.0 (m,2H), 7.0-7.7 (m,13H),8.1-8.15 (m,2H), 8.98 (dd,1H).

EXAMPLE 395-[N-Acetyl-(2-acetoxy-3-(4-diphenylmethylpiperazine-1-yl)propylamino)]quinoline

In 4.5 g of acetic anhydride was dissolved 1.0 g of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropylamino]quinolinesynthesized in Example 27, and the liquid was then allowed to standovernight. Afterward, the liquid was poured into an aqueous sodiumbicarbonate solution, and it was then extracted with methylene chloride.The extract was dried with anhydrous magnesium sulfate and thenconcentrated, and the residue was purified through a silica gel columnchromatograph by the use of ethyl acetate as an effluent solvent toobtain 1.05 g of the desired compound.

NMR δppm (CDCl₃): 1.69 (s,3H), 1.77 (s,3H), 2.1-2.7 (m,8H), 3.37(dd,1H), 3.69 (dd,1H), 4.10 (s,1H), 3.34 (dd,1H), 3.61 (dd,1H), 4.61(dd,1H).

EXAMPLE 405-[N-Acetyl-(3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropylamino)]quinoline

In a mixed solvent of 10 ml of methanol and 5 ml of water were dissolved0.55 g of5-[N-acetyl-(2-acetoxy-3-(4-diphenylmethylpiperazine-1-yl)propylamino)]quinolineand 0.5 g of potassium carbonate, and the liquid was allowed to stand atroom temperature overnight. The liquid was extracted with methylenechloride, and the extract was then dried with anhydrous magnesiumsulfate and was concentrated to obtain 0.5 g of the desired compound.

NMR δppm (CDCl₃): 1.74 (s,3H), 2.1-2.9 (m,10H), 3.4-3.6 (m,1H), 3.8-4.2(m,3H), 7.1-7.8 (m,13H), 8.1-8.3 (m,2H), 8.96-8.99 (m,1H).

EXAMPLE 412-Chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 23-(c), reaction andtreatment were carried out using 1 g of 2-chloro-5-hydroxyquinoline and2.88 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazinesynthesized in Example 23-(b), in order to obtain 1.39 g of2-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline.

NMR δppm (DMSO-d₆): 2.2-2.4 (m,4H), 2.4-2.7 (m,6H), 3.9-4.3 (m,4H), 4.91(s,1H), 6.9-7.7 (m,14H), 8.64 (d,1H).

EXAMPLE 425-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-2-methoxyquinoline

Following the same procedure as in Example 23-(c), reaction andtreatment were carried out using 0.6 g of 5-hydroxy-2-methoxyquinolineand 1.93 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazinesynthesized in Example 23-(b), in order to obtain 1.2 g of5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-2-methoxyquinoline.

NMR δppm (DMSO-d₆): 2.2-2.7 (m,4H), 2.4-2.7 (m,6H), 3.9-4.15 (m,6H),4.19 (s,1H), 4.83 (s,1H), 6.75-6.9 (m,2H), 7.05-7.55 (m,12H), 8.46(d,1H).

EXAMPLE 435-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]isoquinoline

(a) With 40 ml of acetone were mixed 3.55 g of -hydroxyisoquinoline, 3.4g of epichlorohydrin and 5.0 g of potassium carbonate, and the liquidwas then heated under reflux for 6 hours. After the removal of insolublesubstances, the solvent was distilled off, and the resultant residue waspurified through a silica gel column chromatograph. On allowing aneffluent solvent of chloroform:methanol=100:1 to flow therethrough,5-(2,3-epoxypropoxy)isoquinoline which was the desired product wasobtained in an oily state in an amount of 1.6 g.

IR νcm⁻¹ (liq. film): 3480, 2920, 1670, 1580, 1490, 1390, 1280, 1250.

(b) In 20 ml of ethanol were dissolved 0.8 g of the above obtained epoxycompound and 1.0 g of N-diphenylmethylpiperazine, and the liquid wasthen heated under reflux for 2 hours. After the reaction, the solventwas distilled off, and the resultant residue was purified through asilica gel column chromatograph. On allowing an effluent solvent ofchloroform:methanol=50:1 to flow therethrough,5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]isoquinolinewhich was the intended product was obtained in an powdery state in anamount of 0.7 g.

IR νcm⁻¹ (KBr): 3420, 2820, 1620, 1580, 1490, 1450.

NMR δppm (CDCl₃): 2.2-3.0 (m,10H), 3.8 (s,1H), 4.15 (s,2H), 4.25 (s,2H),6.9-7.8 (m,13H), 8.0 (d,1H), 8.5 (d,1H), 9.2 (d,1H).

EXAMPLE 445-[3-(4-(Dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]isoquinoline

In 20 ml of ethanol were dissolved 0.93 g of the epoxy compound preparedin Example 43-(a) and 1.29 g of the piperazine compound prepared inExample 2-(a), and the liquid was then heated under reflux for 2 hours.After the reaction, the solvent was distilled off, and the resultantresidue was purified through a silica gel column chromatograph. Onallowing an effluent solvent of chloroform:methanol=50:1 to flowtherethrough, the desired product5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]isoquinolinewas obtained in an powdery state in an amount of 1.14 g.

IR νcm⁻¹ (KBr): 3400, 2920, 2800, 1580, 1490, 1430, 1390, 1280, 1110.

NMR δppm (CDCl₃): 2.1-3.0 (m,12H), 3.6-4.4 (m,7H), 6.9-7.6 (m,11H), 8.0(d,1H), 8.5 (m,1H), 9.15 (s,1H).

EXAMPLE 455-[3-(4-Diphenylmethylhomopiperazine-1-yl)-2-hydroxypropoxy]isoquinoline

In 20 ml of ethanol were dissolved 0.74 g of the epoxy compound preparedin Example 43-(a) and 0.97 g of N-diphenylmethylhomopiperazine, and theliquid was then heated under reflux for 2 hours. After the reaction, thesolvent was distilled off, and the resultant residue was purifiedthrough a silica gel column chromatograph. On allowing an effluentsolvent of chloroform:methanol=50:1 to flow therethrough, the desiredproduct5-[3-(4-diphenylmethylhomopiperazine-1-yl)-2-hydroxypropoxy]isoquinolinewas obtained in an powdery state in an amount of 1.04 g.

NMR δppm (CDCl₃): 1.8 (t,2H), 2.3-3.3 (m,10H), 4.0 (s,1H), 4.15 (s,3H),4.55 (s,1H), 6.8-7.7 (m,13H), 8.0 (d,1H), 8.5 (dd,1H), 9.15 (s,1H).

EXAMPLE 464-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline

In 50 ml of acetone were dissolved 3.55 g of 4-hydroxyquinoline, 3.4 gof epichlorohydrin and 5 g of potassium carbonate, and the liquid wasthen heated under reflux for 6 hours. After the removal of insolublesubstances, the solvent was distilled off, and the resultant residue wasthen purified through a silica gel column chromatograph.

On allowing an effluent solvent of chloroform:methanol=100:1 to flowtherethrough, 2.1 g of 4-(2,3-epoxypropoxy)quinoline was obtained in anoily state. In 40 ml of ethanol were dissolved 1.6 g of this epoxycompound and 2.0 g of N-diphenylmethylpiperazine, and the liquid wasthen heated under reflux for 2 hours. After the reaction, the solventwas distilled off, and the resultant residue was purified in a silicagel column chromatograph. On allowing an effluent solvent ofchloroform:methanol=50:1 to flow therethrough, the desired product4-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline wasobtained in a powdery state in an amount of 1.5 g.

IR νcm⁻¹ (KBr): 3400, 2800, 1630, 1580, 1490, 1450, 1230, 1010.

NMR δppm (CDCl₃): 2.0-3.0 (m,10H), 3.5-3.9 (m,1H), 3.9-4.6 (m,3H), 5.85(d,1H), 6.9-7.8 (m,14H), 8.1 (d,1H).

EXAMPLE 478-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]isoquinoline

In 15 ml of dried THF were dissolved 80 mg of 8-hydroxyisoquinoline and204 mg of 4-(3-(chloro-2-hydroxypropyl)-1-diphenylmethylpiperazinesynthesized in Example 23-(b), and 68 mg of potassium t-butoxide wasfurther added thereto, followed by stirring at room temperature for 20hours. The reaction liquid was then poured into 15 ml of an aqueoussaturated ammonium chloride solution, and extraction was then performedwith 150 ml of methylene chloride. After drying with an anhydrousGlauber's salt, the solvent was distilled off, and the resultant residuewas purified through a silica gel thin-layer chromatograph. Developmentwas carried out by the use of an effluent solvent ofchloroform:methanol=25:1 for the purpose of separation and purification,with the result that8-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxy-propoxy]isoquinolinewas obtained in an amount of 70 mg.

IR νcm⁻¹ (KBr): 3400, 2800, 1570, 1450, 1390, 1280, 1120.

NMR δppm (CDCl₃): 2.4-3.0 (m,10H), 3.7 (br,s,1H), 4.0-4.5 (m,4H), 6.96(d,1H), 7.1-7.8 (m,13H), 8.56 (d,1H), 9.60 (s,1H).

EXAMPLE 481-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]isoquinoline

In 20 ml of dried DMF was dissolved 1 g of 1-hydroxyisoquinoline, and0.77 g of t-butoxypotassium was further added thereto. The liquid wasthen heated with stirring at 50° C. for 30 minutes. To the reactionliquid was added 1.91 g of epichlorohydrin, and heating was further madewith stirring at 90° C. for 2 hours. The solvent was distilled off underreduced pressure, and ethanol was added to the resultant residue.Afterward, a deposited salt was removed by filtration, and active carbonwas then added to the ethanol solution so as to purify the latter. Theamount of the ethanol solution was then adjusted to 30 ml and 1 g ofdiphenylmethylpiperazine was added thereto, and the liquid was thenheated under reflux for 2.5 hours. The solvent was distilled off, andthe resultant residue was then purified by means of a silica gel columnchromatograph. On allowing an effluent solvent ofchloroform:methanol=50:1 to flow therethrough, the intended product1-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]isoquinoline wasobtained in a powdery state in an amount of 1.94 g.

NMR δppm (CDCl₃): 2.0-2.8 (m,8H), 2.9 (d,2H), 3.4-4.5 (m,5H), 6.5(dd,1H), 6.8-7.9 (m,14H), 8.4 (dd,1H).

EXAMPLE 498-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-quinoline

In 5 ml of dried THF were dissolved 200 mg of 8-hydroxyquinoline and 319mg of the piperazine compound prepared in Example 23-(b), and 120 mg ofpotassium t-butoxide was further added thereto. The liquid was thenstirred at room temperature for 5 days, and 20 ml of a 1 N aqueoussodium hydroxide solution was poured into the liquid, followed byextracting with 100 ml of methylene chloride. Afterward, the methylenechloride solution was washed with a dilute aqueous sodium hydroxidesolution, and was then dried with an anhydrous Glauber's salt. After thesolvent was distilled off, the residue was purified through a silica gelcolumn chromatograph. On allowing an effluent solvent ofchloroform:methanol=50:1 to flow therethrough, the desired product8-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-quinoline wasobtained in a powdery state in an amount of 45 mg.

IR νcm⁻¹ (KBr): 3350, 2800, 1500, 1450, 1320, 1110.

NMR δppm (CDCl₃): 2.2-3.0 (m,10H), 4.1-4.8 (m,4H), 4.9 (br,s,1H),7.0-7.8 (m,14H), 8.15 (dd,1H), 8.85 (d,d,1H).

EXAMPLE 505-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoxaline

In 20 ml of dried DMF was dissolved 1 g of 5-hydroxyquinoxaline, and0.78 g of t-butoxypotassium was further added. Afterward, the liquid washeated with stirring at 50° C. for 30 minutes. After the reaction, 1.9 gof epichlorohydrin was added thereto, followed by heating and stirringat 90° C. for 3 hours. The solvent was distilled off under reducedpressure and water was then added to the resultant residue, and theliquid extracted with 50 ml of chloroform. The chloroform liquid wasdried with an anhydrous Glauber's salt, followed by distilling off, andthe residue was then purified through a silica gel column chromatograph.On allowing an effluent solvent of chloroform:methanol=100:1 to flowtherethrough, 0.28 g of 5-(2,3-expoypropoxy)quinoxaline was obtained inan oily state. In 10 ml of ethanol were dissolved 0.28 g of this epoxycompound and 0.35 g of N-diphenylmethylpiperazine, and the liquid wasthen heated under reflux for 3 hours. After the reaction, the solventwas distilled off, and the resultant residue was then purified by meansof a silica gel column chromatograph. On allowing a solvent ofchloroform:methanol=50:1 to flow therethrough, the desired compound5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoxaline wasobtained in a powdery state in an amount of 0.12 g.

IR νcm⁻¹ (KBr): 3360, 2980, 1600, 1560, 1480, 1460, 1440, 1290, 1100.

NMR δppm (CDCl₃): 2.2-3.2 (m,10H), 3.8 (s,1H), 4.1-4.6 (m,4H), 7.0-8.0(m,13H), 8.7-9.1 (m,2H).

EXAMPLE 515-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinazoline

In 30 ml of dried DMF was dissolved 2 g of 5-hydroxyquinoline, and 1.5 gof t-butoxypotassium was added thereto, followed by heating and stirringat 50° C. for 1 hour. To the reaction liquid was added 4 g ofepichlorohydrin, and the liquid was then heated with stirring at 90° C.for 3 hours. The solvent was distilled off under reduced pressure, andthe resultant residue was then purified by the use of a silica gelcolumn chromatograph. On allowing an effluent solvent ofchloroform:methanol=100:1 to flow therethrough,5-(2,3-epoxypropoxy)quinazoline was obtained in an oily state in anamount of 0.84 g. In 20 ml of ethanol were dissolved 0.84 g of thisepoxy compound and 1.05 g of N-diphenylmethylpiperazine, and the liquidwas then heated under reflux for 3 hours. After the reaction, thesolvent was distilled off, and the resultant residue was then purifiedthrough the silica gel column chromatograph. On allowing the effluentsolvent of chloroform:methanol=50:1 to flow therethrough, the intendedproduct5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinazoline wasobtained in a powdery state in an amount of 0.48 g.

IR νcm⁻¹ (KBr) 3400, 2800, 1610, 1580, 1130.

NMR δppm (CDCl₃): 2.2-3.0 (m,10H), 3.4 (br,s,1H), 2.0-2.3 (m,4H),6.9-7.9 (m,13H), 9.28 (s,1H), 9.70 (s,1H).

EXAMPLE 525-(3-[4-((4-Pyridyl)-phenylmethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using N-[(4-pyridyl)-phenylmethyl]piperazine to obtainthe desired compound.

IR νcm⁻¹ (KBr): 3350, 1620, 1590, 1410, 1370, 1270, 1100, 780.

NMR δppm (CDCl₃): 2.3-3.9 (m,10H), 4.05-4.20 (m,3H), 4.25 (s,1H), 6.85(d,1H), 7.2-7.4(m,8H), 7.58 (t,1H), 7.70 (d,1H), 8.50 (d,1H), 8.55(d,1H), 2.89 (d,1H).

EXAMPLE 532,4-Dimethyl-5-[3-((α,α-diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(a) and (b), reaction andtreatment were carried out using 2,4-dimethyl-5-hydroxyquinolineprepared in Example 5-(b) and N-(α,α-diphenylacetyl)piperazine in orderto obtain the desired compound.

IR νcm⁻¹ (KBr) (HCl salt): 3350 (br.), 1630, 1595, 1430, 1380, 1260,1090, 1025, 735, 690.

NMR 270 MHz (CDCl₃) δppm: 2.10-2.72 (m,5H), 2.63 (s,3H), 2.83 (s,3H),3.30-3.60 (m,3H), 3.60-3.80 (m,2H), 4.00-4.20 (m,2H), 5.19 (s,1H), 6.75(d,1H), 6.99 (s,1H), 7.20-7.40 (m,10H), 7.47 (tr,1H), 7.60 (d,1H).

EXAMPLE 542-Trifluoromethyl-4-methyl-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

The same procedures as in Example 5-(a) and (b) were repeated with theexception that acetylacetone was replaced withα,α,α-trifuloroacetylacetone, in order to perform reaction andtreatment, whereby 2-trifluoromethyl-4-methyl-5-hydroxyquinoline wasobtained.

Furthermore, following the same procedures as in Example 1-(a) and (b),reaction and treatment were carried out using the thus prepared compoundand N-(dipenzosuberane-5-yl)piperazine to obtain the desired compound.

IR νcm⁻¹ (KBr) 2920, 2800, 1590, 1370, 1350, 1330, 270, 1180, 1140, 750.

NMR (CDCl₃) δppm: 2.20-2.90 (m,12H), 2.76 (s,3H), 3.90-4.25 (m,6H),6.95-7.20 (m,9H), 7.55-7.75 (m,3H).

EXAMPLE 552-Trifluoromethyl-4-methyl-5-[3-(4-(α,α-diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedures as in Example 1-(a) and (b), reaction andtreatment were carried out using2-trifluoromethyl-4-methyl-5-hydroxyquinoline prepared in Example 54 andN-(α,α-diphenylacetyl)piperazine in order to obtain the desiredcompound.

IR νcm⁻¹ (KBr): 1630, 1595, 1450, 1430, 1380, 1350, 1270, 1180, 1140.

NMR (CDCl₃) δppm: 215-270 (m,6H), 2.77 (s,3H), 3.40-3.55 (m,2H),3.65-3.80 (m,2H), 4.00-4.30 (m,3H), 5.20 (s,1H), 7.00 (d,1H, J=7.41),7.10-7.50 (m,10H), 7.60-7.80 (m,3H).

EXAMPLE 562-Trifluoromethyl-4-methyl-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedures as in Example 1-(a) and (b), reaction andtreatment were carried out using2-trifluoromethyl-4-methyl-5-hydroxyquinoline prepared in Example 54 andN-diphenylmethylpiperazine in order to obtain the desired compound.

IR νcm⁻¹ (KBr): 2800, 1595, 1450, 1380, 1350, 1330, 1270, 1180, 1140.

NMR δ(CDCl₃) ppm: 2.20-2.90 (m,10H), 2.77 (s,3H), 4.00-4.35 (m,4H), 7.02(d,1H, J=7.92 Hz), 7.10-7.55 (m,10H), 7.55-7.80 (m,3H).

EXAMPLE 57 5-(3-[4-(Bis(4-fluorophenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1(a) andN-[bis-(4-fluorophenyl)methyl]piperazine in order to obtain the desiredcompound.

IR (KBr) νmax cm⁻¹ (HCl salt): 3400, 1630, 1590, 1510, 1410, 1280, 1230.

NMR δppm (CDCl₃): 2.1-2.9 (10H, bm), 4.1-4.2 (3H,m), 6.85-7.75 (12H,m),8.55 (1H,dd), 8.9 (1H,dd).

EXAMPLE 585-(3-[4-((4-Chlorophenyl)-phenylmethyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) andN-[(4-chlorophenyl)phenylmethyl]piperazine in order to obtain thedesired compound.

IR (KBr) νmax cm⁻¹ (HCl salt): 3400, 1630, 1590, 1410, 1380, 1280.

NMR (CDCl₃) δppm: 2.17-2.93 (10H,bm), 4.1-4.3 (4H,m), 6.85 (1H,d),7.16-7.74 (12H,m), 8.55 (1H,dd), 8.9 (1H,dd).

EXAMPLE 59 5-(3-[4-(Bis-(4-methoxyphenyl)methyl)piperazine-1-yl]-2-hydroxypropoxy)quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) andN-[4-bis-(4-methoxyphenyl)methyl]piperazine in order to obtain thedesired compound.

IR νmax cm⁻¹ (KBr): 3400, 1635, 1610, 1595, 1510, 1410, 1280, 1250.

NMR (CDCl₃) δppm: 2.34-2.76 (10H, bm), 3.75 (6H,s), 4.11-4.24 (4H,m),6.80-6.87 (5H,m), 7.26-7.39 (5H,m), 7.55-7.71 (2H,m), 8.57 (1H,d), 8.89(1H,dd).

EXAMPLE 605-[3-(4-(Iminodibenzyl-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) andN-(iminodibenzyl-5-carbonyl)piperazine in order to obtain the desiredcompound.

IR νmax cm⁻¹ (KBr) (HCl salt): 3400, 1640, 1600, 1490, 1415, 1380, 1280.

NMR (CDCl₃) δppm: 2.3-2.4 (2H,m), 2.53-2.61 (4H,m), 3.15 (4H,s), 3.40(4H,m), 4.10-4.22 (3H,m), 6.85 (1H,d), 7.09-7.71 (11H,m), 8.52 (1H,dd),8.90 (1H,dd).

EXAMPLE 612,4-Dimethyl-5-[3-(4-(iminodibenzyl-5-carbonyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 5 andN-(iminodibenzyl-5-carbonyl)piperazine in order to obtain the desiredcompound.

IR μmax cm⁻¹ (KBr) (HCl salt): 3400, 3240, 1640, 1600, 1480, 1440, 1390,1270, 1260.

NMR δppm (CDCl₃): 1.8-2.15 (1H,m), 2.26-2.40 (2H,m), 2.50-2.60 (4H,m),2.64 (3H,s), 2.84 (3H,s), 3.16 (4H,s), 3.40 (4H,s), 4.01-4.20 (3H,m),6.77 (1H,d), 6.99 (1H,s), 7.09-7.62 (10H,m).

EXAMPLE 625-[3-(N'-(Dibenzosuberane-5-yl)ethylenediamino)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) andN-(dibenzosuberane-5-yl)ethylenediamine in order to obtain the desiredcompound.

IR νmax cm-1 (KBr) (HCl): 3400, 2920, 1630, 1590, 1410, 1380, 1280,1100.

NMR δppm (CDCl₃): 2.20-2.59 (2H, bs), 2.60-3.0 (8H,m), 3.56-3.72 (2H,m),4.04-4.25 (3H,m), 4.77 (1H,s), 8.82 (1H,d), 7.08-7.75 (11H,m), 8.53(1H,dd), 8.87 (1H,dd).

EXAMPLE 635-[3-(N,N'-Dimethyl-N'-(dibenzosuberan-5-yl)ethylenediamino-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) andN,N'-dimethyl-N'-(dibenzosuberane-5-yl)ethylenediamine in order toobtain the desired compound.

IR νmax cm⁻¹ (KBr) (HCl salt): 3400, 2920, 1630, 1590, 1470, 1410, 1370,1280, 1100.

NMR δppm (CDCl₃): 2.13 (6H,d), 2.4-2.55 (5H,m), 2.56-2.90 (3H,m),3.90-4.20 (6H,m), 6.85 (1H,d), 6.98-7.75 (11H,m), 8.57 (1H,dd), 8.92(1H,dd).

EXAMPLE 642-Methylthio-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

An epoxy compound was prepared from 2-methylthio-5-hydroxyquinoline inaccordance with the same procedure as in Example 1-(a), and reaction andtreatment were then carried out using this epoxy compound andN-(dibenzosuberane-5-yl)piperazine to obtain the desired compound.

IR νcm⁻¹ (KBr) (HCl salt): 1615, 1600, 1575, 1480, 1440, 1390, 1335,1285, 1250, 1125.

NMR δppm (CDCl₃): 2.20-2.85 (m,12H), 2.67 (s,3H), 3.85-4 20 (m,6H), 6.74(d,1H,J=8.9), 6.95-7.30 (m,9H), 7.40-7.55 (m,2H), 8.26 (d,1H,J=8.9).

EXAMPLE 652-Methylthio-5-[3-(4-(α,α-diphenylacetyl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

An epoxy compound was prepared from 2-methylthio-5-hydroxyquinoline inaccordance with the same procedure as in Example 1-(a), and reaction andtreatment were then carried out using this epoxy compound andN-(α,α-diphenylacetyl)piperazine to obtain the desired compound.

IR (KBr) νcm⁻¹ (HCl salt): 1630, 1580, 1440, 1420, 1390, 1250, 1130,1070, 1020.

NMR 270 MHz (CDCl₃) δppm: 2.15-2.25 (m,1H), 2.35-2.70 (m,5H), 2.68(s,3H), 3.40-3.55 (m,2H), 3.65-3.80 (m,2H), 4.05-4.20 (m,3H), 6.75(d,1H,J=8.4), 7.15-7.35 (m,11H), 7.45-7.55 (m,2H), 8.38 (d,1H,J=8.91).

EXAMPLE 662,4-Dimethyl-5-[3-(N,N'-dimethyl-N'-(dibenzosuberane-5-yl)ethylenediamino)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 5 andN,N'-dimethyl-N'-(dibenzosuberane-5-yl)ethylenediamine in order toobtain the desired compound.

NMR (CDCl₃) δppm: 2.12 (6H,d), 2.40-2.6 (5H,m), 2.65 (3H,s), 2.70-2.90(5H,m), 3.93-4.10 (6H,m), 6.77 (1H,d), 7.00-7.20 (9H,m), 7.45-7.65(2H,m).

EXAMPLE 672,4-Dimethyl-5-[3-(4-diphenylmethylenepiperizine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 5 and4-diphenylmethylenepiperizine to obtain the desired compound.

IR (KBr) νmax cm⁻¹ (HCl salt): 3380, 2900, 2640, 1630, 1600, 1470, 1440,1380, 1270.

NMR (CDCl₃) δppm: 1.74-1.97 (1H,bm), 2.35-2.60 (6H,m), 2.62-2.95(10H,m), 4.05-4.30 (3H,m), 6.80 (1H,d), 7.00 (1H,s), 7.10-7.35 (10H,m),7.45-7.65 (2H,m).

EXAMPLE 685-(3-[N-{3-dibenzosuberane-5-ylidene)propyl}-N-methylamino]-2-hydroxypropoxy)quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) andhydroxydibenzosuberane in order to obtain the desired compound.

IR (KBr) νmax cm⁻¹ (HCl salt): 3360, 2640, 1630, 1590, 1475, 1410, 1370,1270, 1100.

NMR (CDCl₃) δppm: 1.45-2.05 (5H, bm), 2.28 (3H,s), 2.31-2.85 (6H,m),3.2-3.5 (1H,bm), 4.05-4.35 (3H,m), 6.8-7.76 (12H,m), 8.52-8.58 (1H,m),8.89-8.93 (1H,m).

EXAMPLE 69 5-[3-(3,3-Diphenylpropylamino)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) and3,3-diphenylpropylamine to obtain the desired compound.

IR (KBr) νcm⁻¹ : 1610, 1580, 1490, 1460, 1400, 1360, 1315, 1270, 1200,1170, 1140.

NMR 270 (CDCl₃) δppm: 2.43-2.60 (m,2H), 2.80-3.15 (m,3H), 4.90-5.20(m,5H), 6.67 (d,1H,J=7.42), 7.05-7.40 (m,11H), 7.45-7.80 (m,2H), 8.53(d,1H,J=8.4), 8.80-8.95 (m,1H).

EXAMPLE 70 5-[3-(2,2-Diphenylethylamino)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) and2,2-diphenylethylamine in order to obtain the desired compound.

IR (KBr) νcm⁻¹ (HCl salt): 1620, 1580, 1480, 1440, 1400, 1370, 1270,1200, 1170, 1140.

NMR 270 (CDCl₃) δppm: 2.85-3.40 (m,3H), 4.00-4.28 (m,5H), 6.82(d,1H,J=7.42), 7.05-7.40 (m,1H), 7.52-7.72 (m,2H), 8.45-8.55 (m,1H),8.85-8.90 (m,1H).

EXAMPLE 712-Methylsulfonyl-5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

An epoxy compound was prepared from 2-methylsulfonyl-5-hydroxyquinolinein accordance with the same procedure as in Example 1-(a), and reactionand treatment were then made using the thus prepared epoxy compound andN-(dibenzosuberane-5-yl)piperazine to obtain the desired compound

IR (KBr) νcm⁻¹ : 1640, 1610, 1575, 1465, 1450, 1300, 1270, 1160, 1140,1120.

NMR (CDCl₃) δppm: 2.20-2.90 (m,12H), 3.35 (s,3H), 3.90-4.30 (m,6H),6.95-7.25 (m,9H), 7.66-7.82 (m,2H), 8.07 (d,1H,J=8.4), 8.83(d,1H,J=8.91).

EXAMPLE 725-[3-(4-(Xanthene-9-yl)piperazine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using the epoxy compound prepared in Example 1-(a) andN-(xanthene-9-yl)piperazine.

IR (KBr) νcm⁻¹ : 3400, 2800, 1580, 1460, 1440, 1240, 980, 740.

NMR δppm (CDCl₃): 2.3-2.7 (m,10H), 4.0-4.15 (m,3H), 4.83 (s,1H), 6.81(d,1H), 7.1-7.4 (m,9H), 7.56 (t,1H), 7.67 (d,1H), 8.52 (d,1H), 8.88(d,1H).

EXAMPLE 735-[3-(N-Methyl-3-(5-iminodibenzyl)propylamino)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using an epoxy compound prepared in Example 1-(a) anddesipramine in order to obtain the desired compound.

IR KBr νmax cm⁻¹ (HCl salt): 3380, 2640, 1630, 1590, 1485, 1470, 1410,1380, 1280, 1110.

NMR (CDCl₃) δppm: 1.65-1.76 (2H,m), 2.18 (3H,s), 2.37-2.58 (4H,m), 3.11(4H,s), 3.67-3.86 (2H,m), 3.98-4.10 (3H,m), 6.74-6.86 (3H,m), 6.97-7.08(6H,m), 7.27-7.32 (1H,m), 7.48-7.67 (2H,m), 8.42-8.50 (1H,m), 8.81-8.84(1H,dd).

EXAMPLE 745-[3-(4-Diphenylmethylpiperazine-1-yl)-2-hydroxypropylthio]quinoline

In 10 ml of chloroform were dissolved 1.2 g of4-(3-chloro-2-hydroxypropy)-1-diphenylmethylpiperazine prepared inExample 23-(b) and 220 mg of 5-mercaptoquinoline, and 311 mg of DBU wasfurther added thereto. Afterward, the liquid was allowed to stand atroom temperature for 12 days. The reaction liquid wa poured into 20 mlof water and was then extracted twice with methylene chloride. Theresultant organic layer was separated, then dried with an anhydrousGlauber's salt, and was distilled off under reduced pressure. Theresultant residue was purified through a silica gel chromatograph (anAcOEt effluent solvent was used) in order to obtain 130 mg of thedesired compound.

IR max νcm⁻¹ (KBr): 3300, 2520, 1620, 1580, 1420, 1390, 1360, 1290,1070, 910.

NMR δppm (CDCl₃): 2.3-2.7 (m,12H), 3.8-3.9 (m,1H), 4.21 (s,1H), 7.1-7.7(m,13H), 8.00 (dd,1H), 8.75 (dd,1H), 8.94 (dd,1H).

EXAMPLE 755-[3-(4-(Dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxy-propylthio]quinoline

The same procedure as in Example 23-(b) was repeated with the exceptionthat diphenylmethylpiperazine was replaced with4-(dibenzosuberane-5-yl)piperazine, in order to prepare4-(3-chloro-2-hydroxypropyl)-1-(dibenzosuberane-5-yl)piperazine, andreaction and treatment were then carried out using 932 mg of the thusprepared piperazine compound and 270 mg of 5-mercaptoquinoline inaccordance with the same procedure as in Example 74, so that 220 mg ofthe desired compound was obtained.

IR max νcm⁻¹ (KBr): 3300, 2500, 1580, 1390, 1360, 1300, 1070, 860, 760,650, 620.

NMR δppm (CDCl₃) 2.1-2.7 (m,12H), 2.7-2.9 (m,2H), 3.8-4.1 (m,4H),7.0-7.8 (m,11H), 8.00 (d,1H), 8.75 (dd,1H), 8.93 (dd,1H).

EXAMPLE 765-[3-(4-(Dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]-2,4-bis(trifluoromethyl)quinoline

(a) Following the same procedure as in Example 1-(a), reaction andtreatment were carried out using 0.38 g of2,4-bis(trifluoromethyl)-5-hydroxyquinoline, in order to obtain 0.18 gof 5-(2,3-epoxy)propoxy-2,4-bis(trifluoromethyl)quinoline.

NMR δppm (CDCl₃): 2.7-2.8 (m,1H), 2.9-3.0 (m,1H), 3.4-3.5 (m,1H),4.1-4.4 (m,2H), 7.19 (d,1H), 7.81 (t,1H), 7.96 (d,1H), 8.08 (s,1H).

(b) Following the same procedure as in Example 1-(b), reaction andtreatment were carried out using 0.18 g of the above synthesized epoxycompound and 0.16 g of (dibenzosuberane-5-yl)piperazine synthesized inExample 2-(a) in order to obtain 0.3 g of5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-2-hydroxypropoxy]-2,4-bis(trifluoromethyl)quinoline.

NMR δppm (CDCl₃): 2.16-2.90 (m,12H), 3.9-4.3 (m,6H), 7.0-7.3 (m,10H),7.80 (t,1H), 7.94 (d,1H), 8.05 (s,1H).

EXAMPLE 775-[3-(4-(Dibenzosuberene-5-ylidene)piperidine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 1.66 g of 4-(dibenzosuberene-5-ylidene)piperidineand 1.65 g of epoxy compound synthesized in Example 1-(a), in order toobtain 1.32 g of5-[3-(4-(dibenzosuberene-5-ylidene)piperidine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2700, 1645, 1590, 1410.

NMR δppm (CDCl₃): 2.1-2.9 (m,10H), 3.9-4.2 (m,3H), 6.78 (d,1H), 6.86(s,2H), 7.1-7.3 (m,8H), 7.50 (t,1H) 7.63 (d 1H) 8.47 (d 1H), 8.81(d,1H).

EXAMPLE 785-[2-Hydroxy-3-(4-(5-hydroxydibenzosuberane-5-yl)piperidine-1-yl)propoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.78 g of4-(5-hydroxydibenzosuberane-5-yl)piperidine and 0.80 g of epoxy compoundsynthesized in Example 1-(a), in order to obtain 0.99 g of5-[2-hydroxy-3-(4-(5-hydroxydibenzosuberane-5-yl)piperidine-1-yl)propoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2700, 1630, 1590, 1410, 1280, 1105, 790.

NMR δppm (CDCl₃): 1.2-2.6 (m,12H), 2.9-3.05 (m,2H), 3.43-3.52 (m,2H),4.0-4.1 (m,1H), 4.15 (d,2H), 6.82 (d,1H), 7.0-7.2 (m,6H), 7.33 (dd,1H),7.55 (t,1H), 7.65 (d,1H), 7.80 (d,2H), 8.51 (d,1H), 8.86 (dd,1H).

EXAMPLE 795-[2-Hydroxy-3-(4-(5-hydroxydibenzosuberene-5-yl)piperidine-1-yl)propoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 1.60 g of4-(5-hydroxydibenzosuberene-5-yl)piperidine and 1.08 g of epoxy compoundsynthesized in Example 1-(a), in order to obtain 1.41 g of5-[2-hydroxy-3-(4-(5-hydroxydibenzosuberene-5-yl)piperidine-1-yl)propoxy]quinoline.

IR νcm⁻¹ (KBr): 3350, 2700, 1630, 1590, 1410, 1280, 1105, 790.

NMR δppm (CDCl₃): 1.4 (t,2H), 1.7 (t,1H), 2.0 (t,1H), 2.4-3.0 (m,8H),4.0-4.2 (m,3H), 6.79 (d,1H), 6.92 (s,2H), 7.1-7.4 (m,7H), 7.52 (t,1H),7.65 (dd,1H), 7.89 (dd,2H), 8.45 (dd,1H), 8.83 (dd,1H).

EXAMPLE 80 5-[3-(4-(Dibenzosuberane-5-ylidene)piperidine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.41 g of -(dibenzosuberane-5-yliene)piperidineand 0.40 g of epoxy compound synthesized in Example 1-(a), in order toobtain 0.4 g of5-[3-(4-(dibenzosuberane-5-ylidene)piperidine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2920, 1630, 1590, 1410, 1280, 1100, 790.

NMR δppm (CDCl₃): 2.3-3.0 (m,12H), 3.3-3.5 (m,2H), 4.0-4.3 (m,3H), 6.82(d,1H), 6.9-7.2 (m,8H), 7.32 (dd,1H), 7.54 (t,1H), 7.66 (d,1H), 8.52(dd,1H), 8.85 (dd,1H).

EXAMPLE 815-[3-(4-(Dibenzosuberane-5-yl)piperidine-1-yl)-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 1.60 g of 4-(dibenzosuberane-5-yl)piperidine and1.45 g of epoxy compound synthesized in Example 1-(a), in order toobtain 0.97 g of5-[3-(4-(dibenzosuberane-5-yl)piperidine-1-yl)-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2700, 1630, 1590, 1410, 1280, 1105, 790.

NMR δppm (CDCl₃): 2.1-3.0 (m,12H), 3.3-3.5 (m,2H), 4.0-4.3 (m,3H), 6.83(d,1H), 7.0-7.1 (m,8H), 7.33 (dd,1H), 7.54 (t,1H), 7.66 (d,1H), 8.52(d,1H), 8.86 (dd,1H).

EXAMPLE 825-[3-(N-Methyl-N-(3-(5H-10,11-dihydrodibenzo(b,f)-azepin-5-yl)propyl)amino]-2-hydroxypropoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 1.0 g ofH-10,11-dihydro-5-[3-(methylamino)propyl]-dibenzo[b,f]-azepine and 0.67g of epoxy compound synthesized in Example 1-(a), in order to obtain1.07 g of5-[3-(N-methyl-N-(3-(5H-10,11-dihydrodibenzo[b,f]azepin-5-yl)propyl)amino]-2-hydroxypropoxy]quinoline.

IR νcm⁻¹ (KBr): 3380, 2660, 1630, 1590, 1485, 1410, 1280, 1110.

NMR δppm (CDCl₃): 1.7 (m,2H), 2.20 (s,3H), 2.35-2.61 (m,4H), 3.10(s,4H), 3.65-3.80 (m,2H), 3.95-4.15 (m,3H), 4.20-4.35 (m,1H), 6.7-6.9(m,3H), 6.95-7.15 (m,6H), 7.3 (m,1H), 7.45-7.70 (m,2H), 8.45 (m,1H),8.85 (m,1H).

EXAMPLE 835-[3-(4-(Dibenzosuberane-5-yl)piperazine-1-yl)-propoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.63 g of 4-(dibenzosuberane-5-yl)piperazine and0.6 g of quinoline compound synthesized in Example 32-(a), in order toobtain 0.7 g of5-[3-(4-(dibenzosuberane-5-yl)piperazine-1-yl)-propoxy]quinoline.

IR νcm⁻¹ (KBr): 3420, 1640; 1600, 1420, 1380, 1285, 1110.

NMR δppm (CDCl₃): 2.0-2.95 (m,14H), 3.8-4.1 (m,3H), 4.13-4.25 (m,2H),6.83 (d,1H), 7.0-7.2 (m,8H), 7.35 (m,1H), 7.51-7.7 (m,2H), 8.85 (dd,1H),8.9 (dd,1H).

EXAMPLE 84 5-[3-(4-(Diphenylmethylene)piperidine-1-yl)-propoxy]quinoline

Following the same procedure as in Example 1-(b), reaction and treatmentwere carried out using 0.68 g of -(diphenylmethylene)piperidine and 0.55g of quinoline compound synthesized in Example 32-(a), in order toobtain 0.59 g of5-[3-(4-(diphenylmethylene)piperidine-1-yl)-propoxy]quinoline.

IR νcm⁻¹ (KBr): 3400, 2920, 1630, 1590, 1460, 1410, 1375, 1280.

NMR δppm (CDCl₃): 2.1-2.7 (m, 12H), 4.27 (t,2H), 6.85 (d,1H), 7.1-7.4(m,11H), 7.56-7.7 (m,2H), 8.59 (dd,1H), 8.9 (dd,1H).

EXPERIMENTAL EXAMPLE 1 Potentiating Effect of the Compounds onIncorporation of Anticancer Drugs into Drug-Resistant Cancer Cells

Adriamycin resistant strain 2780AD cells of human ovarian cancer A2780cells (A. M. Rogan et al., Science 224, 994-996, 1984) were suspended ata concentration of 1×10⁶ /ml in RPMI-1640 medium supplemented with 5%fetal calf serum, and 1 ml of the cancer cell suspension was dispensedinto each well of a multi-well culture plate (24 wells, 16 cm indiameter) and then incubated at 37° C. in an atmosphere of 5% CO₂. After24 hours incubation, the medium in each well was replaced by 0.5 ml ofRPMI-1640 medium supplemented containing 20 nM ³ H-vincristine (1×10⁴dpm/pmol), 5% fetal calf serum and 10 mM Hepes buffer. Five microlitersof a solution of the compound to be tested, which had been dissolved inDMSO and diluted with serine-phosphate buffer (at a concentration of 1.0microgram/ml or 10.0 micrograms/ml), was added to each well and theincubation was continued at 37° C. in 5% CO₂ for 2 hours. The resultantcells were washed in cold saline-phosphate buffer. In each well wasadded 0.5 ml of 0.2 N NaOH, and the resulting cell suspension in eachwell was independently transferred into a vial and then heated in awater bath at 56° C. for 30-60 minutes to dissolved the cells. Afteradding 4 ml of acid aquazole 2, the amount of ³ H-vincristineincorporated into the cells was determined by a fluid scintillationcounter.

The potentiating effect was expressed by percentage (%) of the amount ofvincristine incorporated into the cells treated with the test compoundcompared to that incorporated into the control cells without treatment.The results are shown in Table 1.

EXPERIMENTAL EXAMPLE 2 Potentiating Effect of the Compounds on Activityof Anticancer Drugs

Adriamycin resistant strain K562/ADM cells of human myeloleukemia K562cells were suspended at a concentration of 2×10⁴ /ml in RPMI-1640 mediumsupplemented with a 5% fetal calf serum, and 2 ml of the cancer cellsuspension was dispensed into each tube (12×75 mm) and then incubated at37° C. in 5% CO₂. After 6 hours incubation, vincristine (0-3,000 ng/ml)and the test compound (0.3, 1 or 3 ng/ml) were added, and the incubationwas continued at 37° C. in 5% CO₂ for 2 hours. The cell suspension wasadded to 9.5 ml of ISTON II, and the number of cells were counted by aCoulter counter to estimate the vincristine concentration at which 50%growth was inhibited, IC₅₀ (ng/ml).

Two cases from the results of the experiments, IC₅₀ value andpotentiating effect, with the compounds given in Table 1 as set forthare given in Table 2. Likewise, the potentiating effect on the activityof drugs was observed with the other compounds in Table 1 (dataomitted).

EXPERIMENTAL EXAMPLE 3 Potentiating Effect on the Activity ofAnticancer-Drugs on Mice Having Vincristine-Resistant Mouse Leukemia

Vincristine-resistant strain P388/VCR cells of mouse leukemia P388 cells(1×10⁶) were peritoneally transplanted into female CDFI mice, and thenvincristine and the test compound given in Table 1 in combination wereperitoneally administered once a day for 5 days.

Survival of animals was observed, and percentage (%) of surviving daysof the animals administered with the test compound to those of thecontrol animals (T/C), were calculated. The results are partially shownin Tables 3(a)-3(f).

A similar effect on survival was observed with the other compounds inTable 1 (data omitted).

                  TABLE 1                                                         ______________________________________                                                     .sup.3 H-vincristine accumulation (%)                            Compound     Concentration of compound (μg/ml)                             (Example #)  1            10                                                  ______________________________________                                        None (Control)                                                                             100          100                                                  1           717          747                                                  2           663          709                                                  3           731          774                                                  4           438          770                                                  5           732          1040                                                 6           1035         1135                                                 7           972          1040                                                 8           394          863                                                  9           721          947                                                 10           642          932                                                 11           735          1073                                                12           568          831                                                 13           517          805                                                 14           119          871                                                 15           840          1072                                                16           850          982                                                 17           730          1040                                                18           743          761                                                 19           374          524                                                 20           794          1054                                                21           727          745                                                 22           723          743                                                 23           723          1604                                                24           146          931                                                 25           858          1376                                                26           177          1111                                                27           1146         1239                                                28           1705         1147                                                29           246          1161                                                30           597          1083                                                31           428          799                                                 32           816          1413                                                33           447          1081                                                34           785          1034                                                35           654          627                                                 36           821          716                                                 37           549          1000                                                38           378          819                                                 39           236          908                                                 40           259          1017                                                41           584          1231                                                None (control)                                                                             100          100                                                 42           624          1011                                                43           531          1297                                                44           636          934                                                 45           307          982                                                 46           142          987                                                 47           322          879                                                 48           215          798                                                 49           213          612                                                 50           559          668                                                 51           534          798                                                 52           379          910                                                 53           658          794                                                 54           253          777                                                 55           452          756                                                 56           321          735                                                 57           572          732                                                 58           619          843                                                 59           561          685                                                 60           643          760                                                 61           519          602                                                 62           525          1125                                                63           773          1130                                                64           425          900                                                 65           297          985                                                 66           488          1071                                                67           730          1065                                                68           671          1097                                                69           738          941                                                 70           252          960                                                 71           501          921                                                 72           112          144                                                 74           626          1024                                                75           587          1064                                                76           130          304                                                 77           1019         1192                                                78           943          1077                                                79           841          963                                                 80           942          1143                                                81           992          1232                                                82           667          1273                                                83           957          1263                                                84           159          878                                                 ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                  IC.sub.50 (ng/ml)*.sup.1                                            Compound  Concentration of compound (μg/ml)                                (Example #)                                                                             0       0.3        1       3                                        ______________________________________                                        1         655     4.3(151.2)*.sup.2                                                                        1.9(342.1)                                                                            1.5(433.3)                               2         655     2.0(330.3) 1.7(388.0)                                                                            1.2(550.0)                               ______________________________________                                         *.sup.1 Vincristine concentration at which 50% of the growth of               adriamycinresistant human myeloleukemia K562 cells (K562/ADM) was             inhibited.                                                                    *.sup.2 Values in parentheses, which indicate effect in potentiating          vincristine activity by test compounds, are multiples of the control. The     calculation was made by dividing the value of IC.sub.50 for the individua     test compound by that for the control (without test compound), 655.      

                  TABLE 3-(a)                                                     ______________________________________                                        Compound                 Average                                              Example                                                                              Concentration                                                                             Vincristine                                                                             surviving T/C*                                   #      (mg/kg)     (ug/kg)   period (days)                                                                           (%)                                    ______________________________________                                        Control                                                                              (none)       0        11.2 ± 1.0                                                                           100                                    None   (none)      100       11.5 ± 0.5                                                                           103                                    1       3          100       12.4 ± 0.2                                                                           111                                    1      10          100       12.2 ± 0.4                                                                           109                                    1      30          100       12.8 ± 0.4                                                                           114                                    2       3          100       12.6 ± 0.2                                                                           113                                    2      30          100       15.2 ± 0.7                                                                           136                                    44     10          100       12.5 ± 0.0                                                                           112                                    44     30          100       13.8 ± 1.0                                                                           123                                    ______________________________________                                         *Rate of life prolongation                                               

                  TABLE 3-(b)                                                     ______________________________________                                        Compound                 Average                                              Example                                                                              Concentration                                                                             Vincristine                                                                             surviving T/C*                                   #      (mg/kg)     (ug/kg)   period (days)                                                                           (%)                                    ______________________________________                                        Control                                                                              (none)       0        10.5 ± 0.6                                                                           100                                    None   (none)      100       11.5 ± 0.4                                                                           110                                     6     30          100       13.4 ± 0.7                                                                           128                                     7     30          100       12.9 ± 0.5                                                                           123                                    11     30          100       12.1 ± 0.5                                                                           115                                    15     30          100       12.3 ± 0.4                                                                           117                                    16     30          100       13.9 ± 1.4                                                                           132                                    18     30          100       13.8 ± 0.4                                                                           131                                    22     30          100       13.9 ± 0.4                                                                           132                                    ______________________________________                                         *Rate of life prolongation                                               

                  TABLE 3-(c)                                                     ______________________________________                                        Compound                 Average                                              Example                                                                              Concentration                                                                             Vincristine                                                                             surviving T/C*                                   #      (mg/kg)     (ug/kg)   period (days)                                                                           (%)                                    ______________________________________                                        Control                                                                              (none)       0        10.3 ± 0.7                                                                           100                                    None   (none)      100       10.8 ± 0.8                                                                           105                                    27     30          100       12.3 ± 0.3                                                                           119                                     5     30          100       12.8 ± 0.8                                                                           124                                    32     30          100       11.3 ± 0.4                                                                           110                                    17     30          100       11.8 ± 1.1                                                                           115                                    35     30          100       11.9 ± 0.7                                                                           116                                    36     30          100       12.6 ± 0.9                                                                           122                                    20     30          100       13.7 ± 1.0                                                                           133                                    21     30          100       12.5 ± 0.6                                                                           121                                    ______________________________________                                         *Rate of life prolongation                                               

                  TABLE 3-(d)                                                     ______________________________________                                        Compound                 Average                                              Example                                                                              Concentration                                                                             Vincristine                                                                             surviving T/C*                                   #      (mg/kg)     (ug/kg)   period (days)                                                                           (%)                                    ______________________________________                                        Control                                                                              (none)       0        11.0 ± 0.4                                                                           100                                    None   (none)      100       10.7 ± 0.4                                                                            97                                     3     30          100       11.0 ± 0.6                                                                           100                                     4     30          100       11.8 ± 0.4                                                                           107                                    41     30          100       13.2 ± 1.8                                                                           120                                    42     30          100       13.9 ± 2.4                                                                           126                                    10     30          100       12.3 ± 1.4                                                                           112                                    12     30          100       12.5 ± 0.5                                                                           114                                    13     30          100       15.3 ± 0.5                                                                           139                                    34     30          100       10.8 ± 0.8                                                                            98                                    ______________________________________                                         *Rate of life prolongation                                               

                  TABLE 3-(e)                                                     ______________________________________                                        Compound                 Average                                              Example                                                                              Concentration                                                                             Vincristine                                                                             surviving T/C*                                   #      (mg/kg)     (ug/kg)   period (days)                                                                           (%)                                    ______________________________________                                        Control                                                                              (none)       0        10.6 ± 0.4                                                                           100                                    None   (none)      100       11.3 ± 0.5                                                                           107                                     8     30          100       12.2 ± 0.6                                                                           115                                     9     30          100       14.2 ± 0.6                                                                           134                                    53     30          100       11.8 ± 0.8                                                                           111                                    55     30          100       12.7 ± 0.3                                                                           120                                    57     30          100       13.1 ± 0.4                                                                           124                                    58     30          100       13.8 ± 1.8                                                                           130                                    59     30          100       13.2 ± 1.2                                                                           125                                    60     30          100       12.4 ± 0.7                                                                           117                                    61     30          100       11.5 ± 0.3                                                                           108                                    ______________________________________                                         *Rate of life prolongation                                               

                  TABLE 3-(f)                                                     ______________________________________                                        Compound                 Average                                              Example                                                                              Concentration                                                                             Vincristine                                                                             surviving T/C*                                   #      (mg/kg)     (ug/kg)   period (days)                                                                           (%)                                    ______________________________________                                        Control                                                                              (none)       0        10.7 ± 1.0                                                                           100                                    None   (none)      100       11.3 ± 0.6                                                                           106                                    77     30          100       13.8 ± 1.2                                                                           129                                    78     30          100       12.8 ± 0.8                                                                           120                                    80     30          100       14.3 ± 0.6                                                                           134                                    81     30          100       13.2 ± 0.9                                                                           123                                    82     30          100       11.2 ± 1.4                                                                           105                                    83     30          100       13.5 ± 0.5                                                                           126                                    84     30          100       13.0 ± 0.7                                                                           121                                    ______________________________________                                         *Rate of life prolongation                                               

Although the invention has been described with reference to preferredembodiments, it is to be understood that variations and modificationswill be apparent to those skilled in the art and are included within theinvention. Such variations and modifications are to be considered withinthe purview and the scope of the claims appended thereto.

What is claimed is:
 1. A compound of the formula [I] ##STR17## in whichA³ represents an oxygen or sulfur atom or an amino or NR³ group, whichis bound to any available position on the condensed ring; B³ represents--(CH₂)_(n) --, ##STR18## or --CO(CH₂)_(n) --; C³ represents ##STR19##D³ represents ##STR20## C³ and D³ together form ##STR21## F³ is a carbonatom, G³ is a nitrogen atom, R¹ and R² each independently represent ahydrogen or halogen atom, a lower alkyl group, amino group, lower alkylamino group, lower dialkyl amino group, a lower alkoxy, lower alkylthio,lower alkylsulfonyl, trifluoromethyl, cyano, nitro, amide or hydroxygroup, wherein R¹ and R² may be on any position available on thecondensed ring or one each on each of the rings or both on the same ringof which the condensed ring is formed; R³ represents a hydrogen atom ora lower alkyl, lower alkanoyl or benzoyl group; R⁴ represents ahydroxyl, lower alkylamino, lower alkoxyl or lower acyloxy group; R⁵ andR⁶ each independently represent a hydrogen atom or a lower alkyl orhydroxyalkyl group; R⁷, R⁸ and R⁹ each independently represent ahydrogen atom or a hydroxy, phenyl, pyridyl, halogenophenyl,alkylphenyl, alkoxyphenyl, aminophenyl, alkylaminophenyl,acylaminophenyl, or hydroxyphenyl group; I³ represents an oxygen atom,##STR22## or a nitrogen atom; J³ represents --(CH₂)_(m) --, --CH═CH--,OCH₂ -- or an oxygen atom, n is 1, 2, 3, 4 or 5 and m is 0, 1 or 2, or apharmaceutically acceptable salt thereof.
 2. A compound of the formula[II] ##STR23## in which A⁵ represents an oxygen or sulfur atom or anamino or NR³ group, which is bound to any available position on thecondensed ring; B⁵ represents --CO(CH₂)_(n) --; C⁵ represents ##STR24##D⁵ represents ##STR25## C⁵ and D⁵ together form ##STR26## E⁵, F⁵, G⁵each represent a carbon atom, R¹ and R² each independently represent ahydrogen or halogen atom, a lower alkyl group, amino group, lower alkylamino group, lower dialkyl amino group, a lower alkoxy, lower alkylthio,lower alkylsulfonyl, trifluoromethyl, cyano, nitro, amide or hydroxygroup, wherein R¹ and R² may be on any position available on thecondensed ring or one each on each of the rings or both on the same ringof which the condensed ring is formed; R³ represents a hydrogen atom ora lower alkyl, lower alkanoyl or benzoyl group; R⁵ and R⁶ eachindependently represent a hydrogen atom, or a lower alkyl orhydroxyalkyl group; R⁷, R⁸ and R⁹ each independently represent ahydrogen atom or a hydroxy, phenyl, pyridyl, halogenophenyl,alkylphenyl, alkoxyphenyl, aminophenyl, alkylaminophenyl,acylaminophenyl, or hydroxyphenyl group, I⁵, represents an oxygen atom##STR27## or a nitrogen atom; J⁵ represents --(CH₂)_(m) --, --CH═CH--,OCH₂ -- or an oxygen atom, n is 1, 2, 3, 4 or 5 and m is 0, 1 or 2, or apharmaceutically acceptable salt thereof.
 3. A compound of the formula[III] ##STR28## in which A⁷ represents an oxygen or sulfur atom or anamino or NR³ group, which is bound to any available position on thecondensed ring; B⁷ represents --(CH₂)_(n) --, ##STR29## or C⁷ represents##STR30## D⁷ represents ##STR31## E⁷, F⁷, G⁷ each represent a carbonatom, R¹ and R² each independently represent a hydrogen or halogen atom,a lower alkyl group, amino group, lower alkyl amino group, a lowerdialkyl amino group, a lower alkoxy, lower alkylthio, loweralkylsulfonyl, trifluoromethyl, cyano, nitro, amide or hydroxy group,wherein R¹ and R² may be on any position available on the condensed ringor one each on each of the rings or both on the same ring of which thecondensed ring is formed; R³ represents a hydrogen atom or a loweralkyl, lower alkanoyl or benzoyl group; R⁴ represents a hydroxyl, loweralkylamino, lower alkoxyl or lower acyloxy group; R⁵ and R⁶ eachindependently represent a hydrogen atom or a lower alkyl or hydroxyalkylgroup; R⁷, R⁸ and R⁹ each independently represent a hydrogen atom or ahydroxy, phenyl, pyridyl, halogenophenyl, alkylphenyl, alkoxyphenyl,aminophenyl, alkylaminophenyl, acylaminophenyl, or hydroxyphenyl group,I⁷ represents an oxygen atom, ##STR32## or a nitrogen atom; J⁷represents --(CH₂)_(m) --, --CH═CH--, OCH₂ -- or an oxygen atom, n is 1,2, 3, 4 or 5 and m is 0, 1 or 2, or a pharmaceutically acceptable saltthereof.
 4. A compound of the formula [IV] ##STR33## in which A⁹represents an oxygen or sulfur atom or an amino or NR³ group, which isbound to any available position on the condensed ring; B³ represents--(CH₂)_(n) --, ##STR34## or C⁹ represents ##STR35## D⁹ represents##STR36## C⁹ and D⁹ can together form ##STR37## E⁹, F⁹, G⁹ eachrepresent a carbon atom, R¹ and R² each independently represent ahydrogen or halogen atom, a lower alkyl group, amino group, lower alkylamino group, lower dialkyl amino group, a lower alkoxy, lower alkylthio,lower alkylsulfonyl, trifluoromethyl, cyano, nitro, amide or hydroxygroup, wherein R¹ and R² may be on any position available on thecondensed ring or one each on each of the rings or both on the same ringof which the condensed ring is formed; R³ represents a hydrogen atom ora lower alkyl, lower alkanoyl or benzoyl group; R⁴ represents ahydroxyl, lower alkylamino, lower alkoxyl or lower acyloxy group; R⁵ andR⁶ each independently represent a hydrogen atom or a lower alkyl orhydroxyalkyl group; R⁷ and R⁸ each independently represent a hydrogenatom or a hydroxy, phenyl, pyridyl, halogenophenyl, alkylphenyl,alkoxyphenyl, aminophenyl, alkylaminophenyl, acylaminophenyl, orhydroxyphenyl; group R⁹ represents a pyridyl group; I⁹ represents anoxygen atom, ##STR38## or a nitrogen atom; J⁹ represents --(CH₂)_(m) --,--CH═CH--, OCH₂ -- or an oxygen atom, n is 1, 2, 3, 4 or 5 and m is 0, 1or 2, or a pharmaceutically acceptable salt thereof.
 5. The compound ofclaim 1 wherein R¹ and R² each represents hydrogen atoms and A³ bonds tothe 5-position of the ring.
 6. The compound of claim 2, wherein R¹ andR² each represent hydrogen atoms and R¹ and R² each represent hydrogenatoms and A⁵ bonds to the 5-position of the ring.
 7. The compound ofclaim 3, wherein R¹ and R² each represent hydrogen atoms and R¹ and R²each represent hydrogen atoms and A⁷ bonds to the 5-position of thering.
 8. The compound of claim 4, wherein R¹ and R² each representhydrogen atoms and R¹ and R² each represent hydrogen atoms and A⁹ bondsto the 5-position of the ring.
 9. A pharmaceutical composition for thepotentiation of the effect of anticancer drugs, which compositioncomprises a potentiation-effective amount of a compound of any one ofclaims 1, 2, 3, 4, 5, 6, 7 or 8 as an active ingredient together with apharmaceutically acceptable carrier or diluent.